Tumor immunology and immunotherapy

Question 1

What are the components of the immune system that respond to tumors?

Answer 1

• T cells
• Antibodies
• NK cells
• Macrophages
• Dendritic cells

Question 2

How do T cells respond to tumors?

Answer 2

• CTLs recognize and kill potentially malignant cells that express peptides derived from tumor antigens on class I MHC molecules
• This is enabled by dendritic cells and other APCs, which ingest tumor antigens and display them to CD8⁺ T cells
• CD4⁺ T cells respond by providing cytokines for differentiation of naive CD8⁺ T cells into effector and memory CTLs
• CD4⁺ T cells secrete TNF and IFN-γ to promote the cytotoxicity of CTLs and activate macrophages

Question 3

How do antibodies respond to tumors?

Answer 3

Antibodies may kill tumor cells by:

• Activating the complement
• Antibody-dependent cell-mediated cytotoxicity, in which the Fc receptor–bearing macrophages or NK cells mediate the killing

Question 4

How do NK cells respond to tumors?

Answer 4

• NK cells kill tumor cells that lose class I MHC molecules in an effort to evade the immune system
• This cytotoxicity is mediated by IFN-γ, IL-15, and IL-12

Question 5

How do macrophages respond to tumors?

Answer 5

• M1 macrophages may recognize DAMPs, leading to secretion of cytokines that enhance CTLs
• M1 macrophages can phagocytose tumor cells and kill them similarly to how they kill microbes
• M2 macrophages can contribute to tumor progression by secreting VEGF and TGF-β, leading to angiogenesis

Question 6

What are the mechanisms by which tumors evade the immune system?

Answer 6

• Loss of antigen expression
• Active inhibition of immune responses

Question 7

What is tumor immunoediting?

Answer 7

Selective pressures result in the survival and outgrowth of variant tumor cells with reduced immunogenicitiy

Question 8

What are the proteins that are downregulated in tumor cells to prevent antigen expression?

Answer 8

• Class I MHC molecules
• β₂-microglobulin
• Components of the antigen-processing machinery, e.g. the transporter associated with antigen processing, some of the subunits of the proteasome

Question 9

How do tumors lose immunogenic antigens?

Answer 9

• Tumors have a high mitotic rate and genetic instability, so mutations or deletions in genes encoding tumor antigens are common
• If these antigens are not required for the growth of the tumor or maintenance of the transformed phenotype, these cells will have a growth advantage and be selected for

Question 10

How do tumors actively inhibit the immune system?

Answer 10

• Expression of inhibitory molecules, e.g. PD-L1, a B7 protein that is a ligand for the T cell inhibitory receptor PD-1
• Secreted products of tumor cells suppress immune responses, e.g. TGF-β inhibits lymphocytes and M1 macropahges
• Regulatory T cells and some myeloid cells suppress T cell responses to tumors

Question 11

How can the immune system be non-specifically stimulated to combat tumors?

Answer 11

• Administration of killed bacillus Calmette-Guérin (BCG) vaccine at sites of tumor growth, leading to activation of macropahges that also kill the tumor cells as well as T cell responses
• Administration of cytokines that enhance activation of dendritic cells and tumor-specific T cells, e.g. IL-2, IFN-α for melanoma

Question 12

What is checkpoint blockade removal?

Answer 12

• Blockade of T cell inhibitory molecules
• An antibody specific for CTLA-4, the inhibitory receptor on T cells for B7, is used in melanoma
• Antibody blockade of PD-1 or PD-L1 is effective in ehancing T cell killing of tumors

Question 13

What are the immunotherapeutic methods in treating cancer?

Answer 13

• Non-specific immune stimulation
• Removing checkpoint blockade
• Adoptive cellular transfer
• Vaccination

Question 14

What is adoptive cellular transfer?

Answer 14

Transfer of cultured immune cells that have anti-tumor reactivity into a host with a tumor:

• Immune cells are derived from a cancer patient’s blood or solid tumor and are treated in various ways to expand their numbers and enhance their anti-tumor activity
• Chimeric antigen receptors (CARs) are genetically engineered receptors with tumor antigen–specific binding sites econded by Ig-variable genes and independent signaling domains
• CAR-expressing T cells are produced in vitro and injected into the patient, undergoing proliferation before attacking the tumor

Question 15

How is vaccination used in tumor patients?

Answer 15

• Patients are immunized with tumor antigens specific to their tumor. The antigens are identified by studying tumor-specific CTLs and cloning of the genes encoding those antigens
• Patients can be vaccinated with APCs that are already loaded with antigens, e.g. Provengel/Sipuleucel-T vaccine for prostate cancer
• Vaccination with viral antigens for oncoviruses can decrease incidence of cancer, e.g. HPV vaccines decrease risk of cervical cancer

Question 16

Which branch of the immune system, innate or adaptive, responds to tumors?

Answer 16

Both innate and adaptive immunity