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  • 1. Cellular Components of the Anti-Tumor Immune Response Oct 30, 2003 Julie R. Ostberg, Ph.D. Dept of Immunology Roswell Park Cancer Institute
  • 2. Leukocytes- white blood cells Granulocytes 1. neutrophils 2. eosinophils Plasma 3. basophils Non-granulocytes After centrifugation, leukocytes are found in 4. monocytes the “buffy coat” 5. lymphocytes RBCs
  • 3. Granulocytes (Polymorphonuclear Leukocytes) • Neutrophils (PMNs) – Phagocytic and bactericidal – Most numerous leukocytes in blood • Eosinophils/Basophils – Activated by IL-5 and Ag crosslinking of Fc ε R bound IgE
  • 4. Neutrophils in Tumor Immunology • IL-2 secreting tumors are massively infiltrated with PMNs • Exocytosed granules of PMNs in contact with dying tumor cells E. Di Carlo et al Blood 97:339 (2001)
  • 5. Eosinophils in Tumor Immunology Efficacy of Local Cisplatin/IL-2 administration for treatment of equine sarcoids correlates with eosinophilic infiltrate TJP Spoormakers et al Cancer Immunol Immunother 52:179 (2003)
  • 6. Mast Cells in Tumor Immunology • Reside in connective tissue • Activated by Ag crosslinking of Fc ε R bound IgE • Degranulation releases vasoactive and inflammatory mediators • Accumulation at tumor periphery associated with enhanced tumor growth/ invasion and angiogenesis Reviewed by D. Ribatti et al Br J Hematol 115:514 (2003)
  • 7. Monocytes/Macrophages in Tumor Immunology • Phagocytose opsonized cells/particles • Presents Ags to T cells • Tumor cytotoxic function stimulated with LPS, IFNγ , GM-CSF – Via NO, TNF • Capacity to stimulate angiogenesis may support growth of larger tumors • NO and ROS production suggested to suppress anti-tumor immunity Reviewed by AH Klimp et al Crit Rev Oncol Hematol 44:141 (2002), R Kiessling et al Cancer Immunol Immunother 48:353 (1999)
  • 8. Agents Produced by Innate Immune Cells that are ‘Toxic’ to Tumor Cells • ROIs • NO • Antimicrobial peptides • Acidic agents • Proteolytic enzymes • Pro-inflammatory cytokines/chemokines Note Paradox: Chronic release of these effector molecules may also result in immune cell dysfunction!
  • 9. Lymphocytes •Recognize specific • T-cells Ag determinants •Responsible for – helper CD4+ specificity and – cytotoxic CD8+ memory of the • B-cells adaptive immune – become antibody producing response plasma cells • NK cells – part of the innate immune response
  • 10. B Cell Activation • First signal for activation delivered through Ag receptor (membrane Ig) • Ag gets taken up and processed for presentation to T cells • Activated T cell then provides second signal for B cell activation • Note: some Ags provide two signals (e.g. LPS) without T cell help
  • 11. B-1 cells • Use a distinctive/limited set of gene rearrangements to make Ig receptors • Self-renewing in the periphery • Predominant lymphocyte in the peritoneal cavity (CD5+) • Make Ig responses mainly to polysaccharide antigens • Produce IgM without T cell help
  • 12. ADCC CMC Apoptosis
  • 13. Importance of Fcγ R in Tumor Immunity RA Clynes et al Nature Med 6:443 (2000) • Fc γ RIII = stimulatory – Fc γ R -/- mice lose Ab mediated tumor growth control • Fc γ RIIb = inhibitory – Fc γ R IIb -/- mice have enhanced Ab mediated tumor growth control
  • 14. T cell Activation • First signal for activation delivered through Ag receptor (TCR) • Second signal delivered through CD28 (co- stimulation)
  • 15. Helper T cells (TH) • CD4+ (bind MHC class II) • Influence/direct function of other cells • TH1 – Facilitate “cellular immunity” • Activate Mφ , induce B cells to produce opsonizing IgG2a – Secretion of IL-2, IFN- γ … • TH2 – Facilitates “humoral immunity” • Activate B cells to produce neutralizing IgG1 – Secretion of IL-4, IL-5, IL-10….
  • 16. Cytotoxic T Lymphocytes (CTL) • CD8+ (bind MHC class I) • Naïve cells activated by – Potent APCs (DCs) with high levels of costimulatory molecules – Weaker APCs in the presence of CD4+T cells which provide the costimulatory signals • Activated cell makes IL-2, driving its own proliferation/differentiation • Binding of TCR on activated/effector CTL to target cell MHC:peptide directs the focused release of effector molecules to the target cell
  • 17. T cells in Tumor Immunology CTL Th1 Th2 FasL CD40L Perforin CD40 Granzymes Fas cytokines cytokines Tumor Mφ B cell Direct Killing Ab Production ROI/NO Generation of TAA Production (survivin) specific Autologous CTL [SM Schmidt et al Blood 102:571 (2003)]
  • 18. γ / δ T cells • Most = CD4- CD8 – • Use a distinctive/limited set of gene rearrangements to make γ / δ T CR • TCR binds proteins directly (without MHC class I/II) • Reside in epithelia – Do NOT generally recirculate between blood and Lymph nodes • Knockout mice are more susceptible to skin cancer, suggesting role in immunosurveillance
  • 19. γ / δ T cells in Tumor Immunology Endogenous non-peptidic phosphorylated mevalonate metabolites in tumor cells activate γ / δ T cells – Blocking the activity of crucial enzyme in mevalonate pathway inhibits γ / δ T cell activation – Overproduction of these metabolites suggested to target cells with abnormal metabolisms for immune recognition H-J Gober et al J Exp Med 197:163 (2003)
  • 20. Regulatory T cells (Treg) • Revival of “suppressor T cells” • CD4+ CD25+ • Involved in maintanence of self-tolerance – Suppress proliferation of anti-CD3 stimulated T cells in vitro Reviewed by J-F Bach Nature Rev Immunol 3:189 (2003)
  • 21. Treg cells in Tumor Immunology • Removal of Treg cells evokes effective anti- tumor immunity in mouse models S Sakaguchi et al J Immunol 155:1151 (1995) • Cancer patients display increased CD4+ CD25+ T cell pool in peripheral blood – Patients had received neither immunosuppressive therapy or chemotherapy for 3 mo. AM Wolf Clin Cancer Res 9:606 (2003)
  • 22. Diversity of T cells with Regulatory Functions J-F Bach Nature Rev Immunol 3:189 (2003)
  • 23. NK cells • A.k.a. large granular lymphocytes • Mediate tumor cell cytotoxicity via perforin, TNF- α ( F asL and TRAIL?) • Early producers of IFN- γ (Th1 skewing) • Possess receptors for self molecules that inhibit their activation against “normal” cells – e.g., MHC class I • Activation depends on balance of signals from activating vs. inhibitory receptors – NKG2D, NKp44 = activating (human) – KIR, NKG2A = inhibitory (human)
  • 24. NK cells in Tumor Immunology B16 mouse tumor model reveals IL-12 mediated control of tumor metastasis to be dependent on NK cells – Used anti-NK1.1 Ab to deplete NK cells – Primary s.c. tumor growth not dependent on NK cells S-H Park et al J Immunol 170:1197 (2003)
  • 25. NK/T cells • Express both NK cell markers (NK1.1, CD56) as well as an invariant V α TCR (Vα 1 4 mouse, V α 24 human) • V α TCR recognizes the ligand α- GalCer presented by CD1d α - GalCer Th1 cytokines APC NKT Perforin Granzyme B CD40/L FasL IL-12 M Taniguchi et at Ann Rev Immunol 21:483 (2003)
  • 26. Antigen Presenting Cells • Drive tumor Ag specific immune responses DC Mφ B cell Ag uptake Macropino- phagocytosis Ig receptor cytosis, mediated phagocytosis MHC High upon Inducible Constitutive, expression maturation (activation increases on dependent) activation Co-stimulator High upon Inducible Inducible delivery maturation
  • 27. Dendritic Cells (DCs) • Immature DCs in the periphery take up Ag (e.g., Langerhans’ cells in epidermis) • Activation associated maturation and migration to draining LN • Mature DCs present Ag to T cells – MHC class II +, B7+ • Most potent APC for naïve T cells
  • 28. DCs in Tumor Immunology High DC infiltration in clinically resected non-small cell lung cancer specimens correlated with better prognosis N Inoshima et at Clin Cancer Res 8:3480 (2002)
  • 29. DC Subsets • Myeloid DCs – Express CD11b – Derived from monocyte precursors – Activated by GM-CSF • Lymphoid DCs – Express CD8a – Derived from plasmacytoid precursors – Activated by IL-3 – Produce IL-12 and prime Th1 responses – Potential role in peripheral tolerance Note: maturation status or activation/suppression events may direct whether DC = activating or tolerising
  • 30. Lymphoid DCs in Tumor Immunology Lymphoid DCs transduce a tolerogenic signal – Spleen derived lymphoid DCs pulsed with Ag bearing irradiated cells were adoptively transferred into naïve mice – Recipient mice were then challenged with Ag – DCs that were unable to crossprime (β 2 M KO) were not tolerogenic TA Ferguson et at J Immunol 168:5589 (2002)
  • 31. DC subsets continued • DC1 (human) drive Th1 response – mature DC – CD8 α + B7.1+ • DC2 (human) drive Th2 response – Immature DC – CD8 α - B7.2+ • Plasmacytoid DCs (DC2?) – CD4+ IL-3R+ – Display markers/morphological features of plasma cells – Produce large amounts IFN- α / β upon exposure to viruses – Only DC subset shown to be directly activated by CpG DNA (via TLR-9)
  • 32. Immunity and Cancer http://press2.nci.nih.gov/sciencebehind/immune/immune31.htm