general pathology

1. EFFECT OF TUMOR ON
HOST AND TUMOR
IMMUNOLOGY
Dr Ramesh R
Dept of PEDODONTICS AND
PREVENTIVE DENTISTRY

2. CONTENTS
INTRODUCTION
EFFECT OF TUMOR ON HOST
• LOCAL EFFECTS
• HORMONAL EFFECTS
• SYSTEMIC EFFECTS
IMMUNOLOGY OF CANCER
REFERNCES

3. INTRODUCTION
• In simple terms Neoplasia is defined as a mass of tissue formed as a
result of abnormal, excessive, uncoordinated, autonomous and
purposeless proliferation of cells.
• Whether benign or malignant these tumors exert some effects on
the host tissue with difference only in the severity of those effects
between benign and malignant conditions.
• On the contrary the body exhibit some responses to the tumor tissue
as well.
• In this seminar, these effects of tumor growth on the body and the
body’s response to the growth are being discussed

4. TUMOR-HOST INTERRELATIONSHIP
2 FEATURES
• EFFECT OF TUMOR ON HOST
• HOST RESPONSE AGAINST TUMOR

5. EFFECT OF TUMOR ON HOST
LOCAL
EFFECTS
Compression
Mechanical
obstruction
Tissue destruction
Infarction
Ulceration
hemorrhage
HORMONAL
EFFECTS
Hypoglycemia
Hyperthyroidism
Hypercalcemia
Cushing’s syndrome
Polycythemia
SYSTEMIC
EFFECTS
Cancer cachexia
Fever
Anorexia
Paraneoplastic
syndrome

6. LOCAL EFFECTS
• COMPRESSION
Eg pituitary adenoma leads to severe endocrinopathy
small benign tumor of Ampulla of Vater leads to biliary
obstruction
• MECHANICAL OBSTRUCTION
eg benign and malignant tumors of gut produce
mechanical obstruction of intestine

7. • TISSUE DESTRUCTION
malignant tumors infiltrate and destroy
the vital structures
• INFARCTION, ULCERATION, HEMORRHAGE
caused more by malignant tumors
secondary bacterial infection may supervene.
eg large tumors in mobile organs like Ovarian tumors may
undergo torsion and produce infarction and hemorrhage.

8. HORMONAL EFFECTS
• Common in benign tumors
eg Adenoma of islet of Langerhans cause fatal hypoglycemia
thyroid adenoma causes hyperthyroidism
parathyroid adenoma causes hypercalcemia and osteoporosis

9. SYSTEMIC EFFECTS
I CANCER CACHEXIA
• Kakos means bad
• Hexia is condition
• Its also called wasting syndrome

10. • In cancer patients there is progressive loss of body weight leading to
lean body mass accompanied by profound weakness, anorexia and
anemia- CACHEXIA
• It’s a combination of asthenia( weakness) and anorexia
• Seen in end stage of cancer
• Positive risk factor for death
• More seen in upper GIT and pancreatic cancer
• Exact mechanism is not known but not due to increased nutritional
demands of the tumor

11. • Thought to be related to cytokine production by tumor cells
TNF alpha ( cachectin )
Excess mobilisation of suppress appetite
fat from tissue storage
CACHEXIA

12. • OTHER FACTORS
proteolysis inducing factors
lipid mobilising factors
( increase the catabolism of muscle and adipose tissue)
Lipid mobilising factor is suspected to be inducing protein degradation in
skeletal muscle by upregulation of ubiquitin- proteasome pathway and
lipolysis in adipocytes.
TREATMENT
• Improve appetite using appetite stimulants to ensure adequate intake of
nutrients.
• Removal of tumor is the definitive treatment.

14. FEVER
• Fever of unexplained origin may be presenting feature in some
malignancies such as Hodgkin’s disease, adenocarcinoma kidney,
osteogenic sarcoma etc
• Exact mechanism is unknown
• The tumor cells themselves must be elaborating pyrogens

15. ANOREXIA
• Common problem in cancer patients
• Due to abnormalities in taste and central control of appetite
• Calorie expenditure and BMR often remains high despite of reduced
food intake
• In cancer cachexia there is equal loss of fat and muscle.

16. PARANEOPLASTIC SYNDROME
• These are a group of conditions developing in patients with
advanced cancer
• 10-15 % of advanced cancer patients develop one or more of the
syndromes included in the PNS
• Rarely it will happen as an early manifestation of a latent cancer.

17. HOST RESPONSE AGAINST TUMORS
CELLULAR IMMUNITY
• CTL (cytotoxic T lymphocytes)
• NK cells
• Macrophages
HUMORAL IMMUNITY
• Antibody production by the host against host tumor cells or their
constituents for tumor antigens

18. • Body’s immune system can recognize tumor cells as non - self and
attempt to destroy them and limit the spread of cancer.
• Following observations provides basis for this concept.
1. Certain cancers evoke significant lymphocytic infiltrates composed
of immunocompetent cells
2. Rarely a cancer may spontaneously regress partially or completely
under the influence of host defence mechanism.
3. It is highly unusual to have primary and secondary tumors in the
spleen due to its ability to destroy the growth and proliferation of
the tumor cells.
4. Immune surviellance exists is substantiated by increased frequency
of cancers in immunodeficient host eg: in AIDS patients

19. HOST IMMUNE RESPONSE EVASION BY TUMOR CELLS
• Selective outgrowth of antigen- negative variants
• Loss or reduced expression of histocompatibility antigens
• Lack of costimulation
• Immunosuppression
• Antigen masking
• Apoptosis of cytotoxic T cells

20. TYPES OF GENES THAT CONTROL CANCER
• Four types
1. Growth – promoting proto oncogenes
2. Growth – inhibiting tumor suppressor genes
3. Genes that regulate programmed cell death( apoptosis)
4. Genes involved in DNA repair

21. Immunology of cancer can be discussed under the following
• TUMOR ANTIGENS
• ANTITUMOR IMMUNE RESPONSES
• IMMUNOTHERAPY

22. TUMOR ANTIGENS
• In order for the immune system to react against a tumor, the latter
must have antigens that are recognized as foreign.
• A number of alterations in gene expression occur in cells during
tumorigenesis.
• Tumorigenesis may lead to expression of new antigens (neoantigens)
or alteration in existing antigens that are found on normal cells.

23. Classification of tumor antigens
Two categories
BASED ON THEIR PATTERNS OF EXPRESSION
• TUMOR SPECIFIC ANTIGENS- present only on tumor cells and
not on any normal cells and are unique or specific for a particular
tumor.
• TUMOR ASSOCIATED ANTIGENS – Present on tumor cells and
also on some normal cells from where the tumor originated.

24. • It is now known that TSAs and TAAs can both be present on normal
cells and categorisation into TSA and TAA does not hold true.
• Thus presently distinction of tumor antigens is based on their
recognition by the host immune cells , ie CD8+T cells , and by the
molecular structure of the tumor antigens.
• Current classification is as follows:

25. Based on their molecular structure and source
• Oncoproteins from mutated oncogenes.
• Protein products of tumor suppressor genes.
• Over expressed cellular proteins.
• Abnormally expressed cellular proteins.
• Tumor antigens produced from viral oncoproteins.
• Tumor antigens from randomly mutated genes.
• Oncofetal antigens.
• Altered glycolipids and glycoproteins.
• Cell type- specific differentiation antigens.

26. ONCOPROTEINS FROM MUTATED GENES AND TUMOR
SUPPRESSOR GENE
• Derived from the products of mutant proto oncogenes , tumor
suppressor genes, or other mutated genes. ( beta – catenin, RAS, p53
and CDK4 genes)
• Synthesized in the cytoplasm of tumor cells.
• Enter the class I MHC antigen processing pathway and be recognized
by CD8+ Tcells.
• They may enter class II MHC pathway and be recognized as CD4+ T
cells also.

27. OVEREXPRESSED PROTEINS
• Tumor antigens may be normal cellular proteins that are excessively
expressed in tumor cells and elicit immune responses.
• Eg: Tyrosinase, is expressed on MELANOMAS.
HER2/neu protein overexpressed in breast cancer.
ABNORMALLY EXPRESSED PROTEINS
• Cellular proteins present on some cells is abnormally expressed on
the surface of tumor cells of cancer.
• Eg: MAGE expressed on surface of melanoma, cancers of lungs,
liver, stomach etc
other examples are GAGE , BAGE, RAGE(renal tumor antigen)

28. ONCOFETAL ANTIGENS
• proteins that are expressed at high levels on cancer cells and in normal developing
fetal but not adult tissues.
• They are excellent markers in tumor diagnosis.
• Carcino- embryonic antigens(CEA)
Normally expressed during fetal life on fetal gut. Seen in GIT, pancreas, biliary
system and cancer breast
• Alpha feto protein( AFP)
Normally expressed in fetal life. Seen in hepatocellular carcinoma.
ANTIGENS PRODUCED BY ONCOGENIC VIRUSES
• Oncogenic viruses such as HPV, EBV, HBV produce proteins that are recognized
as foreign by the immune system.
• Viral oncoproteins of HPV in cervical cancer and EBNA proteins of EBV in
Burkitt’s lymphoma

29. ALTERED CELL SURFACE GLYCOLIPIDS AND GLYCOPROTEINS
• Expression of higher than normal levels and/or abnormal forms of surface
glycoproteins and glycolipids.
• Diagnostic markers and targets for therapy.
• These altered molecules include gangliosides, blood group antigens and
mucins.
• These include CA-125 – expressed on ovarian carcinomas
• CA-19-9 = expressed on carcinoma in pancreas & biliary tract
• MUC-1 = expressed on breast carcinomas.

30. CELL TYPE SPECIFIC DIFFERENTIATION ANTIGENS
• Tumors express molecules that are normally present on the cells of
origin
• Important in identifying the tissue of origin of the tumor
• These antigens are called differentiation antigens because they are
specific for particular lineages or differentiation stages of various cell
types.

32. TUMOR IMMUNOLOGY
• Cancer immunology is a branch of immunology that studies
interactions between the immune system and cancer cells.
• It is a field of research that aims to discover cancer
immunotherapies to treat and retard progression of the disease
• The immune response, including the recognition of cancer-
specific antigens , forms the basis of targeted therapy (such
as vaccines and antibody therapies) and tumor marker-
based diagnostic tests.

33. EVIDENCE FOR TUMOR IMMUNITY
• Regression of metastasis after removal of primary tumor
• Infiltraton of tumor by lymphocytes and macrophages
• Lymphocyte proliferation in draining sites of cancer
• Direct demonstration of tumor specific T cells and
antibodies in patients.
• Increased cancer risk after immunosuppression and
immunodeficiency

34. Immunosurveillance
• Formulated in 1957 by Burnet and Thomas.
• proposed that lymphocytes act as sentinels in recognizing and
eliminating continuously arising, nascent transformed cells.
• Cancer immunosurveillance appears to be an important host
protection process that decreases cancer rates through inhibition
of carcinogenesis and maintaining of regular cellular homeostasis.

35. CANCER IMMUNOEDITING
Describe the effects of immune system
 in preventing tumor formation
In sculpting the immunologic properties of tumors to select tumor
cells that escape immune elimination.
Many tumors do elicit an immune response due to tumor antigens
Many tumors evade host immune response through several
mechanisms.
three main phases: elimination, equilibrium and escape.

36. Elimination
• first phase of elimination involves the initiation of an
antitumor immune response.
Cells of the innate immune system recognize the presence of a growing tumor, when it
begins the local tissue damage.
recruiting cells of the innate immune system (e.g. natural killer
cells, macrophages and dendritic cells ) to the tumor site.
• second phase of elimination, newly synthesized IFN-gamma
induces tumor death.
production of chemokines CXCL10, CXCL 9 and CXCL 11. These chemokines play an
important role in promoting tumor death by blocking the formation of new blood
vessels.

37. • third phase, natural killer cells and macrophages transactivate one
another via the reciprocal production of IFN-gamma and IL 12.
This again promotes more tumor killing by these cells via apoptosis
• final phase of elimination, tumor-specific CD4+ and CD8+ T cells
home to the tumor site and the cytotoxic T lymphocytes then destroy
the antigen-bearing tumor cells which remain at the site.

38. Equilibrium and escape
• Tumor cell variants which have survived the elimination phase enter
the equilibrium phase. In this phase, lymphocytes and IFN gamma
exert a selection pressure on tumor cells which are genetically
unstable and rapidly mutating.
• Tumor cell variants which have acquired resistance to elimination
then enter the escape phase.
• In the escape phase, tumor cells continue to grow and expand in an
uncontrolled manner and may eventually lead to malignancies

39. CANCER IMMUNOLOGY AND IMMUNOTHERAPY
• Immunotherapy has been used as a novel means of treating cancer.
Both active and passive means of stimulating the non-specific and
specific immune systems have been employed, in some cases with
significant success.

40. • ACTIVE IMMUNOTHERAPY
In this, the host actively participates in mounting an immune response
• Specific activation is achieved by using vaccines:
i) Hepatitis B vaccine
ii) Human Papilloma virus (HPV) vaccine
• Nonspecific activation is achieved by immunization with:
i) Bacillus Calmette-Guerin (BCG)
ii) Corynebacterium parvum
These activate macrophages to be tumoricidal.

41. • PASSIVE IMMUNOTHERAPY
This involves transfer of preformed antibodies, immune cells and
other factors into the hosts.
Specific:
i) Antibodies against tumor antigens (e.g. Her2/Neu for treatment of
breast cancer)
ii) Antibodies against IL-2R for Human T lymphotropic virus (HTLV-
1)-induced adult T cell leukemia
iii) Antibodies against CD20 expressed on non Hodgkin’s B cell
lymphoma.
iv) Antibodies conjugated to toxins, radioisotopes and anti-cancer
drugs have also been used. These enter the cells and inhibit protein
synthesis.

42. • Nonspecific:
i) Adoptive Transfer of lymphocytes:
Lymphokine-activated killer (LAK) cells which are IL-2 activated T and NK cells.
Tumor-infiltrating lymphocytes (TIL)
ii) Dendritic cells pulsed with tumor antigens may induce tumor-specific T cell
responses.
iii) Cytokines
• IL-2: Activates T cells/NK cells expressing IL-2 receptors. This is used in the
treatment of renal cell carcinoma and melanoma
• IFN-alpha: This induces MHC expression on tumors and used in the treatment of
hairy B cell leukemias
• IFN-gamma: This increases class II MHC expression; used in the treatment of
ovarian cancers.
• TNF-alpha: This kills tumor cells.
• iv) Cytokine gene transfected tumor cells may also be used which can activate T or
LAK cell-mediated anti-tumor immunity.

43. REFERENCE
• OXFORD TEXTBOOK OF PATHOLOGY- Mc GEE VOL 1
• TEXT BOOK OF PATHOLOGY- HARSHMOHAN, 4th EDITION
• WIKIPEDIA