Seminars in Cancer Biology xxx (2005) xxx–xxx


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T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx                                               9




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T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx                                               11

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T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx                                            13

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  1. 1. Seminars in Cancer Biology xxx (2005) xxx–xxx Review Immune suppression in cancer: Effects on immune cells, mechanisms and future therapeutic intervention Theresa L. Whiteside ∗ University of Pittsburgh Cancer Institute, Department of Pathology, School of Medicine, Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213, USA Abstract Evidence indicates that the healthy immune system is necessary for control of malignant disease and that immune suppression associated with cancer contributes to its progression. Tumors have developed strategies to successfully evade the host immune system, and various molecular and cellular mechanisms responsible for tumor evasion have been identified. Certain of these mechanisms target immune anti- tumor effector cells. Dysfunction and apoptosis of these cells in the tumor-bearing host creates an immune imbalance that cannot be corrected by immunotherapies aimed only at activation of anti-tumor immune responses. Reversal of existing immune dysfunction(s) and normalization of lymphocyte homeostasis in patients with cancer needs to be a part of future cancer immunotherapy. Therapeutic strategies are being designed to correct the immune imbalance, deliver adequate in vivo stimulation, transfer effector T cells capable of in vivo expansion and provide protection for the immune effector cells re-populating the host. Survival of these cells and long-term memory development in patients with malignancy are necessary for improving clinical benefits of cancer immunotherapies. © 2005 Elsevier Ltd. All rights reserved. Keywords: Cancer; Immune dysfunction; Lymphocyte apoptosis; Tumor escape; Immune therapies Contents 1. Host immune competence and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2. Is tumor progression helped by immune cells? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3. Inflammation and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4. How tumors evade the host immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Mechanisms of tumor evasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Reversal of immune dysfunction as a goal of cancer immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7. Conclusions and future prospects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1. Host immune competence and cancer to cancer. However, standard tests for measuring immune competence to tumor-associated antigens (TAA), similar to The involvement of the host immune system in control of those available for the assessment of responses to bacte- cancer progression has been suspected but remained incon- rial, viral or fungal antigens, have not been available. Also, clusive for many years. This is because of the lack of convinc- TAA are largely self-antigens and, therefore, TAA-specific ing evidence for a direct link between cancer development immune responses, whether cellular or humoral, are weak and lower immune competence in individuals who succumb and difficult to measure. Innate immunity, which according to the immune surveillance theory is responsible for early ∗ Tel.: +1 412 624 0096; fax: +1 412 624 0264. detection and elimination of malignant cells [1,2], may be E-mail address: whitesidetl@upmc.edu. inefficient in patients who develop malignancy. Evidence is 1044-579X/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2005.07.008 YSCBI-633; No. of Pages 13
  2. 2. 2 T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx convincing that individuals who are older, who have been on can now be measured in the circulation or tissues of patients immuno-suppressive medications over prolonged periods of with cancer using tetramers and flow cytometry [16]. For time or have underlying immune abnormalities, such as an example, we have obtained quantitative estimates of wild- autoimmune disease or a chronic infection (e.g., AIDS) are type sequence (wt) p53 peptide-specific T cells in HLA-A2+ particularly at risk of malignancy [3,4]. Aside from genetic patients with head and neck cancer (HNC) as well as healthy predisposition to cancer [5] or previous viral infections, such age matched controls [17]. While the frequency of T cells spe- as hepatitis, Epstein Barr virus, or herpes virus infections or cific for wt p53 peptides is higher in the peripheral circulation HIV, all of which are associated with the development of spe- of HNC patients than normal controls (NC), T-cell precursors cific cancer types [3,4], most common risk factors for cancer with TCR able to recognize such peptides are detectable in are age, poor nutrition, stress, smoking and excessive alcohol blood of most HLA-A2+ normal donors [17]. Similar results consumption [6,7]. All of the above are also associated with are available for other tumor-associated peptides in patients more or less pronounced abnormalities in the immune system with other cancers and NC cohorts [18,19]. Functional ex [8]. vivo assays, such as proliferation, cytotoxicity or cytokine Testing for immune competence in populations at high production in response to tumor-associated peptides, confirm risk for malignancy has not been routinely performed. There these phenotypic data, although ex vivo responses to these are indications, however, that a loss of immune competence epitopes are often weak and require in vitro sensitization may be an important risk factor. For example, low natural (IVS) with antigen-presenting cells (APC) and exogenous killer (NK) activity has been reported in familial breast cancer cytokines. Taken together, it is clear that T lymphocyte pre- patients as well as their clinically asymptomatic first degree cursors capable of responding to self-antigens, which are relatives [9]. Other studies support the conclusion that mem- often over-expressed in tumors, are detectable albeit at low bers of cancer families have lower levels of natural cytotoxic frequencies in the circulation of most individuals. Such T activity than age-matched individuals without cancer in first lymphocytes are enriched in tumor tissues [20]. Antibodies degree relatives [10,11]. These studies suggest that among to TAA are also often detectable in patients with cancer [21] the unaffected family members, persons with lower NK cell and have been used as a biomarker of prognosis, as is the case activity may be at higher risk of cancer [11]. In combination with, e.g., Abs to p53 in a subgroup of HNC patients who have with evidence for significantly depressed levels of NK cell a particularly poor prognosis [22]. The available data are con- activity reported for cancer patients with advanced disease, sistent with the presence of TAA-reactive precursor T cells these studies implicate persistently low NK cell activity as a in most individuals. However, tolerance to self prevents the risk for developing malignancy. generation of effective anti-tumor immune responses early Also, delayed type hypersensitivity responses (DTH) to on, when tumors first arise. It has been suggested that an recall antigens were found to be absent in individuals who absence of a strong “danger” signal at this time contributes later developed a malignancy [12]. However, these are spo- to the ability of newly forming tumors to avoid recognition radic or anecdotal reports that have not been uniformly by the host immune system [23]. The host is immunocom- accepted as evidence for a lack of immune surveillance in petent but tolerance to self prevents generation of effective individuals at high risk of cancer. Such evidence is better anti-tumor immunity. sought in animal models of tumor growth, where immu- nization with a relevant tumor epitopes slows or completely inhibits tumor progression and prolongs survival [13]. Also, 2. Is tumor progression helped by immune cells? animals that are deficient in immune cell subsets or genet- ically altered to eliminate molecular signals necessary for Pre-malignant and early tumor lesions are generally immune responses have been shown to be highly susceptible well infiltrated with immune cells, largely T lymphocytes, to cancer development [14]. This type of evidence is taken to macrophages and dendritic cells (DC), although B-cell for- mean that the host immune competence in respect to innate mations resembling lymphoid follicles are sometimes present as well as adaptive immunity is important and perhaps nec- [24,25]. These immune cells, tumor-infiltrating lymphocytes essary for cancer prevention. (TIL), are considered to be a component of an inflamma- A more convincing argument can be made for the role of tory host response to the tumor. Over the years, consider- the immune system in control of tumor progression than its able evidence has accumulated indicating that: (a) despite prevention. Both in animal models of tumor growth and in their activation phenotype, TIL are functionally compro- humans with cancer, it is clear that the host usually makes mised and (b) TIL are enriched in TAA-specific memory an immune response to the tumor. Tumor-specific cytolytic T cells (reviewed in [26]). Therefore, TIL accumulate in T lymphocytes (CTL) and IgG antibodies specific for tumor response to the tumor-initiated “signals” and, unlike other epitopes are detectable in cancer-bearing hosts, using sensi- inflammatory infiltrates, contain immune cells specific for tive modern technologies. In particular, the tetramer technol- a variety of peptides expressed by tumor cells. It has been ogy has contributed to our ability to detect and estimate the suggested that TIL elaborate cytokines and growth factors frequency of T cells specific for tumor epitopes [15]. T cells necessary for tumor growth [27], and that tumors produce able to recognize MHC class I- or class II-restricted peptides chemotactic factors that actively recruit mononuclear cells,
  3. 3. T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx 3 mainly lymphocytes and macrophages in humans, to tumor for anti-tumor effects as well as evidence for tumor-favoring sites [28]. Whether this recruitment is orchestrated by the trophic functions. Which of these effects prevail may be deter- tumor or is generated by surrounding tissue cells in response mined by the tumor and not by the host, as discussed below. to the tumor is currently an unanswered question. It has been suggested that the recruited cells, activated in response to local “danger signals” might be a source of trophic fac- 3. Inflammation and cancer tors for the tumor, but fail to exercise anti-tumor functions. In support of this hypothesis, recent data indicate that TIL Tissue trauma normally engenders infiltration into tis- are capable of producing cytokines in response to TAA, sue of inflammatory cells and production of the variety of although their anti-tumor effector functions are either weak cytokines or growth factors suppressing or promoting cellular or absent. proliferation. Most human tumors are infiltrated by mononu- In pre-malignant lesions such as dysplasias or carcinomas clear cells throughout various stages of their progression. in situ (CIS), cells forming these lesions may be antigenically Sustained inflammation at tumor sites leads to release of sol- indistinguishable from normal tissue cells, although genetic uble factors and reactive oxygen species (ROS), which can abnormalities are already present [29]. It is recognized that contribute to generation of dysplastic changes in the geneti- clonally expanding tumor cells are genetically unstable and cally altered, initiated tissue cells. If inflammation becomes readily acquire chromosomal aberrations [29]. If these tumor persistent, e.g., is driven by cell death and necrosis, the cells are recognized by the host immune system, they are cytokine cascade that evolves could mediate either augmen- eliminated. This process of immune selection leads to the out- tation or suppression of local immune responses, depending growth of tumor cells that are genetically altered but resistant on the cellular makeup of the microenvironment. When trans- to immune detection systems. Immune selection may, in fact, formed cells, interacting with inflammatory cells and growth promote growth of tumors resistant to immune intervention. factors (e.g., TNF- ) at sites of chronic inflammation con- Therefore, the role of the immune system in host protection tinue to proliferate, the persistent inflammatory process may from malignancy or in control of tumor progression remains become a crucial step in carcinogenesis. Many cancers have controversial and may be dependent on characteristics of the been associated with persistent inflammation: lung carcino- individual tumor. mas with asbestosis or silicosis; colon cancer with inflam- The role of immunity in tumor metastasis is also disputed. matory bowel disease; pancreatic cancer with pancreatitis; To metastasize, the tumor must possess certain unique charac- oral squamous cell carcinoma with gingivitis and so on [34]. teristics, including the capability to penetrate the endothelium If inadequately cleared bacterial or viral infections are the and acquire mobility within tissues as well as lymphatics or cause of chronic inflammation, strong “danger signals” are blood vessels [30]. Not surprisingly, solid tumor cells appear generated in situ, including LPS, dsRNA, CpG DNA, which to be able to adopt the phenotypic characteristics of lymphoid engage toll-like receptors (TLR) on macrophages (MØ), and cells that enable them to migrate using exactly the same mech- induce massive release of ROS, chemokines, cytokines and anisms [31]. This phenomenon of “masquerading” provides enzymes from MØ and neutrophils [35]. Transformed, genet- yet another example of how tumors use the immune cells to ically unstable tissue cells undergoing clonal expansion in their own advantage. At the same time, it is recognized that this microenvironment have an opportunity for accumula- circulating tumor cells are particularly sensitive to lysis by tion of additional genetic alterations. It is well known that natural killer cells or monocytes [32]. In the presence of anti- some cancers are associated with or preceded by uncon- tumor Abs, these effector cells of innate immunity would also trolled infections with pathogens and chronic inflammation, be able to mediate antibody-dependent cellular cytotoxicity e.g., gastric cancer with Helicobacter pylori, cervical carci- (ADCC), thus efficiently eliminating tumor targets [33]. A noma with HPV, liver cancer with hepatitis B and C viruses, tumor cell that manages to avoid such immune intervention Kaposi’s sarcoma with HSV-8 or adult T-cell leukemia with in the peripheral blood or lymphatic circulation and arrives human T-cell lymphotropic virus, and others. Recently per- at a new tissue site is undoubtedly dependent on the local formed studies in cytokine knock out (KO) mice have shown microenvironment for growth factors and structural support that pro-inflammatory cytokines, e.g., TNF- , play a key by the extracellular matrix (ECM). It has been speculated that role in inducing carcinogenesis, probably acting via the tumor-specific immune cells responding to TAA can produce NF B pathway [36]. However, it should be remembered such growth factors, thus promoting metastasis formation. that immune surveillance, presumably with elimination of Again, the picture that emerges has the host immune system expanding transformed cells is occurring at the same time. performing a dual role of tumor elimination or tumor promo- Therefore, the tenuous balance that exists between immune tion, perhaps depending on local circumstances and signals surveillance and immune promotion is likely to shift, depend- delivered by the tumor. More aggressive tumors might be ing on the signals existing in situ as well as the host ability more successful in subverting the microenvironment, includ- to modulate these signals. In this scenario, cancer progresses ing immune cells, to subserve tumor needs. when the host’s immune system becomes incapable of curtail- The current view of the host immune system responding ing chronic inflammation and initiating the healing process. to the arising or progressing tumor is conflicted by evidence Thus, Dr. H. Dworak’s description of the tumor as “a wound
  4. 4. 4 T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx that does not heal” is a particularly astute appraisal of this recognized by CTLs. To illustrate these mechanisms, a muta- situation [37]. tion in the p53 protein, which inhibits proteasome-mediated generation of wt p53264–272 , abolishes the possibility for a CTL response to this normally immunogenic peptide in some 4. How tumors evade the host immune system patients with HNC [42]. Similarly, down-regulation or muta- tion in TAP1 or TAP2 prevents normal processing of TAA Human tumors, like viruses, have evolved an elaborate in HNC [41] or in melanoma cells [43]. Such examples offer assembly of tricks designed to fool the immune system [38]. a glimpse of perturbations that accumulate in tumor cells, In fact, molecular mechanisms used by tumors to neutralize resulting in a loss of recognition by tumor-specific T cells. immune cells are “borrowed” from viruses [38]. In general, The most frequent abnormality seen in tumor cells tumors employ two strategies to avoid recognition: they either involves changes in expression of classical HLA class I anti- “hide” from immune cells thus avoiding recognition or they gens [44]. As previously shown, these changes range from a proceed to disable or eliminate immune cells. total loss of HLA class I molecules to more selective down- It has been recognized for a long time that tumors are adept regulation of HLA-A, B or C locus expression [44]. The at shedding surface antigens or down-regulating expression frequency of HLA class I antigen loss or down-regulation of key molecules necessary for interactions with immune has been found to range between 16 and 80% for the various cells (reviewed in [39]). In this way, tumors can evade the tumor types analyzed by immunohistochemistry (IHC), using host’s immune response by being (a) poor stimulators of T mAbs recognizing monomorphic HLA determinants [39]. cells or (b) poor targets for tumor-specific T cells (CTL). These changes have been less evident in breast or prostate Expression of molecules such as TAA, HLA class I molecules carcinomas and are most frequently observed in renal cell or antigen processing machinery components (APM) is often carcinoma (RCC) and melanoma [39]. While methods for down-regulated or altered in tumor cells [40]. As a result of detection of HLA class I expression in various tumors are abnormalities in the APM components, which might include dependent on IHC and thus may be subject to experimental their down-regulation, absence or mutation [41], peptides bias, it is notable that down-regulation or absence of HLA are not generated from TAA or are generated in a form class I antigen expression or APM component expression, not allowing for the formation of HLA class I-peptide com- appears to be biologically and clinically significant. Thus, plexes recognized by T cells [41]. Tumors are not effective the presence of these abnormalities has been related to shorter antigen-presenting cells, and they frequently mis-process and survival in patients with HNC, as recently reported [41,45]. mis-represent processed TAA, so that immunogenic peptides Another aberration frequently seen in tumor cells involves cannot be made or are defective and thus do not fit into the down-regulation of co-stimulatory molecule expression on HLA class I groove. In this case, the trimolecular complex, the cell surface [46]. One reason that the tumor cannot func- HLA class I-chain- 2 m-peptide, is absent from the tumor cell tion as an efficient APC may be that it is unable to deliver surface. Alternatively, the peptide-HLA molecule complex is a co-stimulatory signal (signal 2) that is necessary for pro- formed and presented but in a configuration that cannot be ductive interactions with T lymphocytes. Down-regulation of Table 1 Immunosuppressive factors produced by human tumorsa 1. The TNF family ligands: induce leukocyte apoptosis via the TNF family receptors (reviewed in [76]) FasL Fas TRAIL TRAIL-R TNF TNFR1 2. Small molecules Prostagladin E2 (PGE2 ) Inhibits leukocyte functions through increased cAMP [112] Histamine Inhibits leukocyte functions through increased cAMP [112] Epinephrine Inhibits leukocyte functions through increased cAMP [112] INOS Promotes or inhibits Fas-mediated apoptosis by regulation of NO levels [112] H 2 O2 Has pro-oxidant activity, increases cAMP levels, causes apoptosis in NK cells, inhibits tumor- specific CTL [112] 3. Enzymes Indoleamine 2,3-dioxygenase (IDO) Suppresses T-cell responses [113] Arginase I Impairs T-cell functions, decreases chain expression [114] 4. Cytokines TGF- Inhibits perforin and granzyme mRNA expression; inhibits lymphocyte proliferation [115] IL-10 Inhibits production of IL-1 , IFN- , IL-12 and TNF [116,117] GM-CSF Promotes expansion of immunosuppressive tumor-associated macrophages [118] 5. Tumor-associated gangliosides Inhibit IL-2 dependent lymphocyte proliferation or induce apoptotic signals [119] a A partial list of immunosuppressive factors selected to demonstrate their diversity and a wide spectrum of effects on immune cells.
  5. 5. T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx 5 co-stimulatory molecules, including members of the B7 fam- host immune cells. As indicated above, tumors can evade the ily [46], on tumor cells leads to unresponsiveness based on host’s interference by being poor stimulators of immune cells MHC-1-restricted antigen presentation without transmission as well as by being poor targets, which are not recognized of the critical co-stimulatory signal to leukocytes. by immune cells. In addition, tumors actively interfere with Tumors are also known to directly interfere with the host functions and even survival of immune cells by employing a immune system. They either produce and release factors that variety of mechanisms. modulate functions of immune cells or induce apoptosis of these cells. Table 1 is a partial list of various tumor-derived immunosuppressive factors. As can be seen, even this partial 5. Mechanisms of tumor evasion list is long and includes a broad range of biologic effector molecules: several distinct receptor–ligand systems, small Mechanisms responsible for immune cell dysfunction in molecular species, cellular enzymes, soluble cell compo- patients with cancer are numerous and varied, as illustrated nents and cytokines/chemokines. This diversity indicates that in Fig. 1. In addition to a wide variety of soluble immuno- tumors are incredibly adept in their ability to debilitate host suppressive factors (TGF , IL-10, ROS, enzymes, inhibitory immune responses. Whether all of these factors are selec- ligands such as FasL or TRAIL, as listed in Table 1) that are tively employed in vivo at various stages of tumor progression released by tumor cells or other cells in the tumor microenvi- or are produced by some tumors but not others has been a sub- ronment, suppressor cell populations, i.e., regulatory T cells ject of intense and continuing debate. For example, it could be (CD4+CD25) or myeloid-derived suppressor cells have been readily concluded that more aggressive tumors elaborate sev- shown to play a key role in down-regulation of anti-tumor eral different inhibitory molecules or secrete them at higher host immunity [47,48]. levels than less aggressive tumors. However, a formal demon- Generally, immunosuppressive effects of tumors are best stration of this hypothesis is lacking. seen locally, at the tumor site. Functional aberrations of TIL While it is likely that early stages of oncogenesis are freshly isolated from human tumors are well documented in accompanied by a combination of tumor-trophic and anti- the literature [26]. Most TIL are activated T cells containing tumor effects in a large part mediated by infiltrating immune variable proportions of CD8+ and CD4+ T cell subsets, which cells, the balance of interactions between the host immune are almost exclusively CD45RO+ memory T cells [26,49]. In cells and tumor probably changes with time. Once the tumor comparison to autologous PBL or those isolated from tissues is established, it begins to orchestrate its escape from the distant from the tumor, TIL have been consistently found Fig. 1. A schematic representation of various mechanisms responsible for tumor escape. Reproduced with additional details from reference [39].
  6. 6. 6 T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx to be poorly responsive or unresponsive to traditional T-cell activating stimuli [49–51]. While unresponsive to mitogens or antigens, TIL are able to secrete cytokines. However, the profile of cytokines TIL produce may not be equivalent to that in normal T cells. TIL in situ do not produce IL-2 or express IL-2R [52,53], and translation of IL-2 mRNA was found to be defective in TIL isolated from breast carcinoma [52]. It has been suggested that the paucity of Th1 cytokines (i.e., IL-2, IFN- and IL-12) at the tumor site or tumor-draining lymph node as well as the prevalence of Treg cytokines (i.e., IL-10 or TGF- ), appear to condition evolving TA-specific T cells toward the less efficacious Th2 or Treg functional phe- notypes. In fact, in patients with malignant disease, TIL have been shown to display a predominant Type-2 or T-reg func- tional phenotype associated with the local production of IL-4 or IL-10, respectively, rather than the mixed Type-1/Type-2 responsiveness observed in normal donors [54]. Therefore, a cytokine imbalance is one of the mechanisms responsible for Fig. 2. Circulating CD8+ T cells in patients with cancer bind Annexin V. immune deviation seen at the tumor site. The data were obtained with freshly-drawn peripheral blood of patients with Alterations in systemic TAA-specific T cell immunity HNC and age-matched NC by multicolor flow cytometry. A significantly also occur in patients with malignant disease. In the early higher proportion of CD3+CD8+ T cells bind Annexin V in the patients 1990’s Mizoguchi et al. [55], studying dysfunctional T cells than in NC. from long-term tumor bearing mice, demonstrated a marked decrease in the expression of CD3 chain, and of p56lck as Among less known but clearly important immunosuppres- well as p59fyn tyrosine kinases, all of which play a critical role sive effects tumors mediate is the ability to induce T-cell in the signal transduction events that lead to T cell activation apoptosis [76]. Studies involving TUNEL staining of TIL [56]. These changes were accompanied by a decreased tyro- and Annexin V binding to circulating T cells suggest that sine kinase phosphorylation and diminished calcium influx. CD8+ rather than CD4+ T cells selectively undergo apop- These findings provided for the first time a molecular basis for tosis at the tumor site and in the peripheral circulation of T cell dysfunction in cancer patients. More recent studies in patients with cancer [77]. The proportion of CD8+Fas+ T patients with malignant disease confirmed these initial obser- cells that bind Annexin V is significantly increased in the vations in murine models. In this regard, T cells and NK cells circulation of patients with cancer relative to age-matched from approximately half of the patients with carcinoma of the normal controls (Fig. 2). Thus, the fate of CD8+ and CD4+ head and neck [56–58], breast [59], colon [60], kidney [61], T-cell subsets may differ due to their divergent sensitivity to ovary [62] and prostate [63], non-Hodgkins lymphoma [64], apoptosis. Also, the effector subpopulations of CD8+ T cells Hodgkins lymphoma [65], cervix [66,67] and melanoma (e.g., CD8+CD45RO+CD27− and CD8+CD28−) appear to [68,69] demonstrate a decreased CD3 chain expression and be preferentially targeted for apoptosis in patients with cancer a decreased in vitro response to antigens or mitogens. We [78]. Absolute numbers of circulating T cell subsets are low have also demonstrated that circulating T cells are biased in in patients with cancer [79]. Taken together, these findings their cytokine profile or otherwise functionally compromised suggest that a loss of effector T cell function through targeted in patients with malignant disease [70,71]. Importantly, alter- apoptosis might severely compromise anti-tumor functions of ations in circulating T cell function, as determined by CD3 the host immune system and contribute to tumor progression chain expression, proliferative index or NF B activity, are [77]. It also results in the aberrant lymphocyte homeostasis associated with the extent of alterations in TIL function and characterized by a rapid turnover of T cells, especially CD8+ with tumor stage [71–73]. These observations suggest that T cells [80]. CD3 chain expression may be a marker of immune compe- Different mechanisms may account for the high frequency tence in patients with malignant disease, and that individuals of T-cell apoptosis observed in patients with cancer. Binding who have normal CD3 chain expression are most likely to of Fas ligand (FasL) to the Fas receptor has been known respond favorably to biotherapy [56]. It is noteworthy that for some time to induce apoptosis of T cells responding to changes in signal transduction molecules are not limited to autologous antigens and maintain tolerance to normal tis- CD3 chain. Kolenko et al. demonstrated that JAK-3, a tyro- sue antigens. Furthermore, chronically stimulated T cells sine kinase associated with the chain, a common element to are likely to undergo activation-induced cell death (AICD) IL2, IL4, IL7 and IL15 cytokine receptors, was also decreased mediated by the Fas/FasL pathway, or they may die because in T cells from RCC patients [74]. Moreover, T cells from appropriate cytokines are not secreted [81]. AICD is induced RCC patients also had a diminished ability to translocate by repeated or chronic antigenic stimulation, and neither co- NF Bp65 [70,75]. stimulatory molecules nor Bcl-2 family members can rescue
  7. 7. T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx 7 T cells from AICD. In this regard, tumor cells produce and for T-cell differentiation, proliferation and memory devel- secrete a variety of TAA, and TIL, LNL or peripheral T cells opment [89]. Therefore, if TADC are not able to perform in patients with cancer are subject to chronic or repeated anti- normally, as suggested by data in the literature [89], or if they genic stimulation, and the majority express CD95 on the cell also undergo apoptosis in situ, then TADC–TIL interactions surface [57,82]. Such chronic or acute systemic dissemina- are not likely to be optimal for generating productive TA- tion of TAA may result in an excess of Ag and “high dose” specific immunity. The mechanisms responsible for induction tolerance of specific T and B cells, making them particularly of apoptosis and protection of different DC subpopulations susceptible to AICD. and DC precursors from death signals are poorly understood. A somewhat different but related mechanism may be envi- The molecular pathways that may be involved include: (i) sioned, in which the tumor not only induces lymphocyte down-regulation of the anti-apoptotic Bcl-2 family proteins dysfunction, including the reduced ability to produce IL-2 in DC [89,90]; (ii) accumulation of ceramides which may and IFN- [53,83], but also capitalizes on the expression of interfere with PI3K-mediated survival signals [91], or (iii) TNF family receptors on its own surface. A variety of freshly production of nitric oxide (NO) species by tumor cells which harvested or cultured human tumor cells have been found to suppresses expression of cellular inhibitors of apoptosis pro- express mRNA for FasL as well as surface and/or cytosolic teins (cIAPs) [92] or cFLIP. Analysis of gene and protein FasL protein (reviewed in [81]). In addition, microvesicles expression in DC and DC precursors in the tumor microen- (MV), which are presumably derived from tumor cells and, vironment has demonstrated that expression of several intra- contain biologically active membrane form (42 kDa) of FasL cellular signaling molecules is reproducibly altered in DC are present in sera of patients with cancer, including those co-incubated with tumor cells, including IRF2, IL-2R , Mcl- with HNC, ovarian carcinoma and melanoma [84–86]. These 1, and small Rho GTPases among others [93]. It appears that structures can mediate apoptosis of Fas + lymphocytes at sites both intrinsic and extrinsic apoptotic pathways are involved distant from tumor lesions. Therefore, tumors that express in tumor-induced apoptosis of DC, as determined by an Fas-ligand or shed Fas-ligand-containing MV into serum increased resistance to apoptosis of DC genetically-modified could induce apoptosis in T cells infiltrating the tumor site as to over-express XIAP, Caspase 8, Bcl-xL or FLIP. In addition, well as circulating T cells, and thus effectively escape from recent reports confirm that TADC are functionally defec- the effector arm of the immune response [76]. On the other tive, especially in their antigen-presenting capacity [94]. This hand, Fas-expressing malignant cells are themselves resistant is likely due to defective maturation of DC in the tumor to apoptosis. Some of the mechanisms identified include the microenvironment, possibly mediated via tumor-derived vas- over-expression of key anti-apoptotic proteins such as two cular endothelial growth factor (VEGF) [95]. Alternatively, members of the inhibitors of apoptosis (IAP) family (sur- in vitro demonstration that tumor-derived gangliosides inter- vivin and ML-IAP), FLICE inhibitory proteins (FLIP), Bcl-2 fere with expression of inducible proteasomal APM com- and the ability to produce inducible nitric oxide synthetases ponents in DC explains yet another mechanism tumors have (iNOS) which may play a role in inhibiting apoptosis. adapted to facilitate their escape. Moreover, tumor-associated The Fas/FasL pathway inducing receptor- and/or macrophages (TAM) also exhibit functional defects rela- mitochondria-mediated apoptosis of activated T cells [82] tive to their counterparts in tumor-uninvolved inflammatory is only one example of the receptor–ligand interactions lesions in the same patients [96]. contributing to tumor escape. Inhibitory receptor–ligand Finally, the presence of regulatory immune cells, which pairs known to be involved include members of the B7: are known to accumulate at the tumor site [47] but are CD28 superfamily such as CD28: CTLA-4, ICOS: ICOSL also detectable in the peripheral circulation of patients (inducible costimulator) or PD: PD-L1/PD-L2 (program with cancer, has been emphasized as another factor con- death-1). Receptor–ligand pairs of this superfamily play a tributing to tumor escape. Lymphoid (CD4+CD25+) and/or key role in regulating T-cell activation and tolerance [87]. myeloid (CD34+ immature, antigen-presenting) suppres- Expression of the ligand on tumor cells allows for interac- sor cells down-regulate functions of immune effector cells, tions with its receptor on immune effector cells, inducing presumably via cytokine (IL-10, TGF- ) secretion [97], functional paralysis or death [87]. Antibodies specific for the as part of a normal process of controlling autoimmunity. ligand on tumor cells have been shown to protect T cells and Because tumors express self-antigens, suppressor cells may enhance CTL-mediated tumor death in animal models [87]. be recruited to tumor sites to dampen immune responses to An additional mechanism that may also explain the dys- self. In murine models, these cells have been shown to prevent function, and ultimately, death of T cells in situ might result autoimmune disease [98] and to inhibit generation of tumor- from the functional impairment in alternate effector cells that specific T-cell responses [97]. Depletion of CD4+CD25+ T accumulate within tumor sites, tumor-associated dendritic cells has been shown to promote tumor rejection in mice [99]. cells, and TADC [88,89]. TADC not only process and present Regulatory cells are best defined by their suppressive func- TA, but are important sources of IL-1, IL-12, IFN- , IL-15, tion and, thus, in the absence of reliable phenotypic markers IL-18, IL-23 and IL-27, among other cytokines. They are are difficult to study in humans. Defined as Foxp3+, CTLA- also rich in co-stimulatory molecules (CD80, CD86, OX40, 4+, GITR+ T-cell subsets, they appear to be enriched among 4-1BBL) necessary as second signals or in growth factors TIL in human tumors and are more frequent in the periph-
  8. 8. 8 T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx eral circulation of patients with cancer than of normal donors phocyte numbers after an episode of lymphopenia. Alterna- [100]. Studies are currently in progress to achieve a better tively, it is possible that elimination of Treg and reversal of understanding of the role and mechanisms of regulatory cell their inhibitory effects on the immune system by low-dose effects on tumor escape from the host immune system. cydophosphamide/fludarabine treatment facilitates survival The mechanisms of escape evolved by human tumors are of transferred T cells. The precise mechanism of these effects varied and ingenious. They appear to target components of is not yet understood but it appears that protection of immune the innate as well as adaptive immune system; they operate cells and their survival are necessary for achieving therapeu- at the local as well systemic levels, and interfere with molec- tic efficacy. Data are also available in support of cytokine ular pathways responsible for the key cellular functions of administration, e.g., IL-2, after T-cell transfers or following immune cells. Furthermore, progressing tumors co-opt tissue anti-tumor vaccines in patients with cancer [101,102]. cells to participate in creating a microenvironment especially Cytokines play a key role in regulation of lymphocyte sur- unfavorable for immune interventions in situ. As a result of vival [103]. The largest amount of experience is with IL-2, these mechanisms, tumors have become adept at avoiding which not only prolongs survival of transferred CD8+ T cells immune surveillance, and it might be predicted that their but also enhances their anti-tumor activity [104]. In particu- escape from the host’s immune system is likely to be dif- lar, low nontoxic doses of IL-2 administered with transferred ficult to overcome by immune therapies. antigen-specific T cell lines have been shown to promote in vivo persistence and activity of viral-specific as well as tumor antigen-specific CD8+ T cells [104]. In addition, IL-7, IL-15, 6. Reversal of immune dysfunction as a goal of IL-12 and IL-21 are currently gaining attention as promising cancer immunotherapy additions to future immunotherapy protocols. In our hands, cytokines such as IL-2, IL-7, IL-12 and IL- The question of how to best augment and sustain anti- 15 are able to rescue activated T cells from tumor-induced tumor responses during cancer progression has been a focus killing in vitro. As shown in Fig. 3, these cytokines partially of biotherapeutic approaches for a long time. Traditionally, blocked DNA fragmentation in Jurkat cells co-incubated cell-mediated biotherapies used in treating cancer patients with tumor cells (PCI-13). These cytokines also signifi- have been aimed at increasing these responses via activa- cantly inhibited Annexin binding to T cells exposed to tumor tion, amplification of proliferation or re-population of the host cell supernatants or to CH-11 agonistic antibody (Fig. 3). with ex vivo activated anti-tumor effector cells. These strate- The mechanisms of such cytokine-mediated protection of gies referred to as active or passive cellular immunotherapy, immune cells from tumor-induced effects are not known. We respectively, have undergone considerable refinement over recently observed that expression of CCR7 on CD8+ T cells the years. might be important in protection of these cells from apoptosis Active as well as passive immunotherapy of cancer have [105]. CCR7+CD8+ T cells bind significantly less Annexin the best opportunity to succeed in the setting of minimal V than their CCR7− counterparts and express higher levels residual disease, with elimination of Treg prior to ther- of anti-apoptotic Bcl-2 (p < 0.0001) but lower levels of pro- apy, attenuation of apoptosis of activated tumor-specific apoptotic Bax (p < 0.01). Interestingly, patients with HNC T cells and establishment of long-lived anti-tumor mem- whose CD8+ T cells show high spontaneous apoptosis have ory responses. Also, restoration of normal lymphocyte greatly expanded population of circulating CCR7−CD8− T homeostasis is probably an important component of such cells but relatively few CCR7+CD8+ T cells. As the engage- immunotherapy. Rosenberg et al. recently treated cancer ment of CCR7 is necessary for protection from spontaneous patients with adoptively transferred autologous ex vivo cul- apoptosis via the PI3K/AKt pathway [105], it is not surprising tured tumor-specific T cells following lympho-depletion with that CCR7−CD8+ T cells are highly susceptible to apopto- cydophosphamide (30–60 mg/kg × 2 days) plus fludarabine sis in these patients. Because CCR7 is also a differentiation (25 mg/m2 × 5 days) [101,102]. Remarkably, this intentional marker for CD8+ T cells, its absence on a great majority (e.g., lympho-depletion of patients before T-cell transfer promoted over 80%) of CD8+ T cells in patients with HNC indicates extensive proliferation of infused T cells, creating an in that these cells are in the process of terminal differentiation vivo T-cell repertoire capable of exercising powerful anti- which is normally followed by apoptosis [106]. tumor effects and of mediating clinically meaningful tumor A common feature of T cells in the circulation of patients regression [101]. In a very recent study, this same strategy with cancer is low or absent expression of the TCR-associated was reported to induce clinical responses in 50% of treated chain [56]. We have shown preciously that down-regulation patients and documented the persistent presence of tumor- of chain in T cells may be one manifestation of apopto- specific T cells in the periphery [102]. These early results sis induced by interaction of TIL with FasL+ tumor or by indicate that the enhancement of the activity and survival of interactions of circulating CD8+ T cells with FasL+ MV transferred T cells by previous lympho-depletion is thera- [58,107]. Having established a quantitative assay to mea- peutically effective and mediates durable cancer regression sure chain expression by flow cytometry, we measured it in [101,102]. It is possible that this approach takes advantage patients with cancer before and after immune therapies. As of endogenous homeostatic mechanisms that restore lym- indicated in Fig. 4, expression of chain was significantly
  9. 9. T.L. Whiteside / Seminars in Cancer Biology xxx (2005) xxx–xxx 9 Fig. 3. Protective effects of cytokines on activated T cells. (A) Pre-incubation of activated T cells with cytokines protects them from tumor-induced apoptosis as measured in JAM assays. PCI-13 is a tumor cell line, which induces apoptosis in over 60% of T cells in the absence of cytokines. (B) Annexin V binding to T cells is decreased following their incubation with cytokines prior to exposure to PCI-13 supernatants. (C) A decreased Bax/Bcl-2 ratio is observed by flow cytometry in T cells incubated with cytokines prior to exposure to CH-11 antibody, which induces receptor-mediated apoptosis in activated T cells. up-regulated in CD8+ T cells of patients with metastatic tion might translate into improved anti-tumor functions and melanoma treated with IL-2 and histamine dihychrochloride perhaps clinical benefits in these patients. Very preliminary [108]. These results suggest that cytokine therapy tends to findings in our laboratory also suggest that incubation of restore normal signaling in CD8+ T cells and that this restora- freshly-harvested PBMC of cancer patients in the presence of survival cytokines (i.e., IL-2, IL-7, IL-15 or IL-21) tends to diminish their sensitivity to apoptosis, as indicated by lower Annexin binding and a lower Bax/Bcl-2 expression ratio in cytokine-treated vs. untreated CD8+ T cells. Further exper- iments are clearly needed to establish validity and mecha- nisms of cytokine-induced protection of activated CD8+ T cells. It is possible that cytokines mediate their cytoprotec- tive effects through receptor-mediated anti-apoptotic signals or through quite distinct effects on differentiation of effector and memory T cells [109]. Evidence has accumulated indi- cating that common cytokine receptor -chain family − c (CD132) cytokines in particular IL-7 and IL-15 act at vari- ous stages of the immune response to promote proliferation and survival of T cells [103]. These cytokines appear to be especially important in maintenance of memory CD8+ T cells [110]. Therefore, future vaccination or adoptive T-cell trans- fers are likely to favor concomitant cytokine therapy with the goals of protecting effector CD8+ T cells from tumor- mediated dysfunction or death and of restoration of normal lymphocyte homeostasis. Fig. 4. Expression of in circulating CD8+ T cells after therapy with 7. Conclusions and future prospects histamine dihydrochloride and IL-2 in patients with metastatic melanoma (n = 50). Acute and durable effects of therapy on expression relative to base- line expression (stipled line) are illustrated by the boxplots, with medians Cancer immunotherapy has now been in the clinic for indicated by solid lines. many years. One reason for its modest therapeutic record to
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