Tumor Immunology (I):

Cancer Immunosurveillance

& Immunoediting

Masoud H. ManjiliDepartment of Microbiology &

ImmunologyGoodwin Research Building-286

(804) 828-8779

Learning Objectives

Immune surveillance and immune editing of cancer

Immunotherapy of cancer

Goal of Tumor Immunology

The ultimate goal of tumor immunology is to induce clinically effective anti-tumor immune responses that would discriminate between tumor cells and normal cells in cancer patients

Cancer is the second leading causes of death in the US

Types of Cancer

Carcinoma: arising from epithelial tissue, such as glands, breast, skin, and linings of the urogenital, digestive, and respiratory systems (89.3% of all cancers)

Lymphoma, Myeloma: diseases of the lymph nodes and spleen that cause excessive production of lymphocytes (5.4% of cancers)

Leukemia: disease of bone marrow causing excessive production of leukocytes (3.4% of all cancers)

Sarcoma: solid tumors of muscles, bone, and cartilage that arise from the embryological mesoderm (1.9% of all cancers)

Etiology of Cancer

1. Transformation of germline cells: inheritable cancers (<10%, Rb, BRCA1, 2)

2. Transformation of somatic cells: noninheritable cancers (>90%)

Environmental factors:UV (skin cancer), chemicals (lung cancer), pathogens (HPV causes cervical cancer, helicobacter causes stomach cancer)

Genetic Factors

Environmental Factors

Discovery of anti-tumor immune response

Evidence for Tumor Immunity

Spontaneous regression: melanoma, lymphoma

Regression of metastases after removal of primary tumor: pulmonary metastases from renal carcinoma

Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer

Lymphocyte proliferation in draining lymph nodes

Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.

Anti-tumor immunity via cross priming

Tumor Immunology

Cancer immunosurveilance: immune system can recognize and

destroy nascent transformed cells

Cancer immunoediting: tumors tend to be genetically

unstable; thus immune system can kill and also induce changes in the tumor resulting in tumor escape and recurrence

Evidence for Elimination (cancer

immunosurveillance) Mice lacking perforin show an

increased frequency of lymphomas Mice lacking RAG and STAT1 develop

gut epithelial and breast tumors Mice lacking gamma delta T cells are

susceptible to skin tumors induced by topical application of carciongens

Immunosurveillance is against virus-associated tumors rather than against common spontaneous tumors

Elimination or Tolerance? affinity

Elimination: mutated tumor antigens

Elimination: abnormal expression of antigens

Evidence for Equilibrium (occult tumors)

The occurrence of cancer in recipients of organ transplants: melanoma after kidney transplant

Evidence for Escape (detectable tumors)

1) Immune responses change tumors such that tumors will no longer be seen by the immune system: tumor escape

2) Tumors change the immune responses by promoting immune suppressor cells: immune evasion

Escape: immune system sculpts tumors

GM-CSFVEGFMCP-1

MDSC

Summary Environmental factors such as UV,

chemicals, pathogens (viral and bacterial infections)

Immune responses have a dual function: immunosurveillance and immunoediting of tumor (elimination, equilibrium, escape)

Immunoediting: immune responses can change tumors to be hidden from recognition by the immune system and tumors can promote immune suppressor cells: T regs and myeloid-derived suppressor cells (MDSC)

Suggested Reading

Janeway’s Immunobiology, 7th edition: Chapter 15; Pgs. 672-678