Immunity to tumors Tumor antigens Immune system’s reaction to tumor antigens How tumors evade the immune system Immunologic approaches to treatment of cancer

Cancers arise from the uncontrolled proliferation and spread of clones of malignantly transformed cells. Cancer is a major cause of disease and death. About 1 of 5 deaths in industrialised countries is from cancer.

The immune surveillance hypothesis Frank Macfarlane Burnet 1956: The immune system constantly checks our cells, and detects and destroys those that are malignantly transformed.

Contra: Most tumors are not more common in immunodeficient individuals. Exception: Virus-induced tumors.

Four reasons immune surveillance may not work so well:

Tumors are «self», not «foreign» Tumors are «self», not «foreign». They don’t have PAMPs, like pathogens do. 2) Most tumor cells lack HLA class II and costimulatory molecules.

3) Tumors that do not cause inflammation may induce DC- mediated tolerance. 4) Naive T cells circulate in blood, lymph and secondary lymphoid organs, and do not usually enter peripheral tissues.

Sign of immune reaction to tumor: Lymphocytic inflammation.

Demonstration of tumor immunity

Tumor antigens: Tumor-specific Unique to individual tumors Shared among tumors Tumor-associated Viral antigens

Cloned CTL lines identify tumor antigens from melanoma.

Some tumor antigens:

Mutated forms of cellular genes not involved in tumorigenesis: Various mutated proteins in melanomas recognized by CTLs

Products of oncogenes and tumor suppressor genes: Oncogene products: Ras mutations (∼10% of human carcinomas), p210 tyrosine kinase product of Bcr/Abl chromosomal rearrangements (CML). Tumor suppressor gene products: Mutated p53 (present in ∼50% of human tumors).

Unmutated but overexpressed products of oncogenes: HER2/Neu (tyrosine kinase; breast and other carcinomas)

Products of genes that are silent in most normal tissues: Cancer/testis antigens expressed in melanomas and many carcinomas; normally expressed mainly in the testis and placenta

Normal proteins overexpressed in tumor cells: Tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)

Oncofetal antigens: Silenced during development, de-repressed with malignant transformation. Diagnostic tools. Carcinoembryonic antigen (CD66) on many tumors, also expressed in liver and other tissues during inflammation. α-Fetoprotein (also elevated in some non-neoplastic diseases).

Glycolipids and glycoproteins: Gangliosides Mucins

Tissue-specific differentiation antigens: Prostate-specific antigen in prostate carcinomas CD20 on B cell lymphomas

Products of oncogenic viruses: Papillomavirus E6 and E7 proteins (cervical carcinomas) HPV vaccination EBNA-1 protein of Epstein-Barr Virus (EBV-associated lymphomas, nasopharyngeal carcinoma)

Immune responses to tumors Innate immunity NK cells, macrophages Adaptive immunity T lymphocytes, antibodies

NK cells Kill many cells in vitro, especially cells with low expression of MHC class I. ADCC In vivo importance unclear. LAK cells

Macrophages M1 Mφ: Can kill tumor cells M2 Mφ: Can promote tumor growth

The principal mechanism of adaptive tumor immunity is killing of tumor cells by CD8+ CTLs.

Induction of CTL responses to tumors by dendritic cell cross-presentation.

Antibodies Little evidence for in vivo killing of tumors by host antibodies.

Evasion of immune responses by tumors. Tumor editing – tumors become less immunogenic over time.

Intrinsic mechanisms of evasion Loss of antigen expression Lack of costimulators or HLA class II Inhibitory factors

Mechanisms by which tumors escape immune defenses

Extrinsic factors Macrophages with M2 phenotype Regulatory T cells Myeloid-derived suppressor cells

Immunotherapy for tumors: More specific and fewer side effects than current therapies. Stimulation of active host immune responses or Passive immunotherapy

Stimulation of active host immune responses Vaccination with tumor antigens Use of costimulators and cytokines Blocking inhibitory pathways Nonspecific stimulation

Type of Vaccine Vaccine Preparation Tumor vaccines Type of Vaccine Vaccine Preparation Killed tumor vaccine Killed tumor cells + adjuvants Tumor cell lysates + adjuvants Purified tumor antigens Dendritic cell-based Dendritic cells pulsed with vaccines tumor antigens Dendritic cells transfected with genes encoding tumor antigens

Dendritic cell-based tumor vaccines

Enhancement of tumor cell immunogenicity by transfection of costimulator and cytokine genes

Counteracting T-cell inhibition.

Nivolumab: Anti PD1 receptor Ipilimumab: Anti CTLA-4 N Eng J Med July 11 2013 Nivolumab: Anti PD1 receptor Ipilimumab: Anti CTLA-4 (PD1 and CTLA-4 dampen T cell activity.)

Non-specific stimulation by systemic cytokine therapy (a limited success). IL-2 (Melanoma, renal & colon cancer) IFN-α (Melanoma, carcinoid tumor) TNF (Sarcoma, melanoma) GM-CSF (to promote bone marrow recovery)

Passive immunotherapy Adoptive cellular therapy Anti-tumor antibodies

Adoptive cellular therapy LAK cells

Anti-tumor antibodies. Mouse Ig is immunogenic for humans. «Humanization» of mouse Ig.

-monab -ximab -zumab -mumab

Mabs used in cancer treatment in Norway: Alemtuzumab CD52 Chronic lymphatic leukemia Bevacizumab VEGF Several cancer forms Cetuximab, Panitumumab EGFR EGFR+ colorectal cancer

Rituximab, CD20 Non-Hodgkin lymphoma, chronic lymphatic leukemia Ofatumumab Chronic lymphatic leukemia Trastuzumab Her2 Her2+ mamma cancer

Pertuzumab Her2R Her2+ mamma cancer Ipilimumab CTLA-4 Malignant melanoma

Catumaksomab EpCAM + CD3 Malign ascites (ascites is abnormal accumulation of fluid in the abdominal cavity).

Promotion of tumor growth by the immune system: Chronic inflammation Hepatitis B Mutations caused by free radicals Growth factors M2 macrophages (VEGF, TGF-β)