Tumor Immunology

Key questions:

How do tumor cells evade immune systemWhat are the main immune responses to tumor cells?What are the tumor antigens?What are the potential anti-tumor immunotherapies?

23. Tumor Immunology

a. Properties of tumor (transformed) cells(1) Abnormalities in growth and responses to

regulation and apoptosis(2) Induction by carcinogens, viruses;

spontaneous(3) Role of oncogenes (e.g. growth-promoting

oncogenes and oncoproteins)(4) Role of tumor-suppressor genes and genes

that control DNA repair

CORE

CancerCancer is caused by abnormal and invasive growth of tumor cellsIt accounts for 20% of death in industrialized countries.

6 million new cancer patients each year worldwide.

Generally, cancer occurs late in life.

Caused by accumulated mutations in the genes controlling cell growth and death.

Current treatments: surgery, radiation and cytotoxic drugs

Future treatments: small molecule drugs that specifically inhibit tumor cell growth; immunotherapy

Carcinogens induce mutations in DNA:

Chemical carcinogens

Radiation

Oncogenic viruses (& chronic infection/inflammation)

Accumulation of mutations leads to

cancer cells

The growth and lifespan of a typical human tumor

Benign vs. malignant tumorsBreast tumors for example

Malignant cells are more aggressive in growth, and they spread to nearby tissues or to different organs through lymph and blood vessels (Metastasis)

•Carcinomas: epithelial cell tumors (breast, colon, pancreas, and others)

•Leukemia: tumors of circulating cells

•Lymphoma: solid tumors in lymph nodes

•Myelomas: tumors of bone marrow cells

•Sarcomas: tumors of the connective or supportive tissue (bone, cartilage, fat, muscle, blood vessels) and soft tissue.

Terminologies

Viruses are associated with some human cancers

Some viral proteins induce

unchecked proliferation of human cells by targeting genes such as P53 and

Rb

Can tumor cells from a person grow in another person?

Usually, no.

But sometimes, yes.

Largely, it depends on the MHC haplotype of donors and recipients.

How do immune cells detect tumor cells?

CD4, CD8, NK cells and B cells

T cells and antibodies look for tumor antigens, antigens differentially expressed by tumor cells and normal cells.

Tumor antigens:

Changes in the genome of tumor cells can lead to the expression of tumor antigens, which are not (tumor-specific antigens) or less expressed in normal cells (tumor-associated antigens) .

b. Tumor-specific and tumor-associated antigens

(1)Tumor-specific shared antigens: melanoma antigen-1 (MAGE-1); found on melanomas and other transformed cells

(2)Tissue-specific antigens (on normal and transformed cells; such as tyrosinase found on normal and transformed melanocytes)

(3)Antigens resulting from mutation (such as mutations of oncogenes)(4)Over-expressed antigens; antigens expressed at abnormal stage of development(5) Viral antigens

(6) Other cancer indicators:

(a) Oncofetal antigens: Carcinoembryonic antigen (CEA): Colon cancerAlpha-fetoprotein: Liver and testis cancer

(b) Differentiation antigens: Common acute lymphoblastic leukemia antigen (CALLA, also called CD10)

found on cells of acute lymphoblastic leukemia

PSA (Prostate cancer)

CORE

Tumor antigensQualitative and/or quantitative changes in antigen

Tumor Epitope Escape

•Mutation of anchor residues

•Mutation of TCR contact residues•No CTL recognition•Antagonistic Epitope => negative signal to CTL (Altered Peptide Ligand [APL])

•Mutation affecting antigen processing•Within epitope affecting stability of epitope•Outside of epitope efficiency of epitope processing

Tumor antigens

Examples of tumor antigens recognized by CD8 T cells

c. Anti-tumor immunity(1) CMI (TC, TH1 cytokines, NK, macrophage) (2) Humoral (ADCC and activation of complement)(3) "Immunosurveillance": There is an increased frequency

of cancers in immunocompromised individuals, however, most cancers occur in individuals with no overt immunodeficiency. More likely that tumors develop ways of evading the immune system.

CORE

Anti-tumor immunity

Cell-mediated immune response:

CD4 T cells: control other immune cells by cytokinesCD8 T cells: direct lysisNK cells: direct lysisEosinophils: degranulation

Humoral response by B cells:Antibodies to tumor cells 1. facilitate NK cell-mediated lysis of tumor cells2. activate complement reaction

NK cells can attack tumor cells lacking MHC I expression

NK cells

tumor cells

Tumor antigen specific CD4+ and CD8+ T cells

Figure 12-52DCs present tumor antigens to CD4 and CD8 T cells.Membrane fusion allows presentation of tumor Ag to CD8 T cells.

How do tumors evade immune responses?(4)Examples of tumor evasion:

(a)out-growth of antigen-negative variants

(b)loss or reduced expression of MHC proteins

(c)secretion of immunosuppressive cytokines

(d)inducing CTL apoptosis(e) lack of co-stimulatory signals(f) soluble tumor antigens

CORE

Mechanisms of tumor cell evasion of anti-tumor cells

• Defective in one or more of their MHC class I expression(30-50% of tumors are defective in MHC I expression)

• Production of suppressive cytokines (TGF-beta and Th2 cytokines), which suppress cell-mediated immune response

• Lack of co-stimulatory signals

• Out-growth of antigen-negative variants

• Shedding of MHC class I-related chain (MIC), a ligand of NKG2D that is an activating NK cell receptor, by epithelial tumor cells to inhibit NKG2D+ NK cells

Figure 12-50Loss of MHC class I expression in prostate tumor cells

d. Immunotherapy

(1) Non-specific stimulation (adjuvant therapy)(2) Active immunization with tumor antigens; role of co-stimulatory molecules(3) Cytokine therapy(4) Adoptive cellular immunotherapy (LAK cells, TIL)(5) Anti-tumor antibodies (coupled to cytotoxins or radioisotopes)

CORE

Non-specific adjuvant therapy

Introduction of BCG vaccine (killed mycobacterium) into the bladder is a treatment for superficial bladder cancer

This may be because:

Bacterial products or adjuvants increase the T cell response by activating antigen presenting cells and other cells through TLRs. This will also induce co-stimulation molecules and MHC molecules on APCs.

Potential immunotherapies against tumor cells

• Antibody against tumor antigen (immunotoxins and induction of ADCC by NK cells).

• Tumor vaccines: tumors taken at surgery are manipulated ex vivo (out of body) and are used as vaccine. This manipulation includes expressing B7, GM-CSF or IL-12 in tumor cells. Tumor antigens can be used as vaccines too. e.g. CEA (carcinoembryonic antigen), HSP (heat shock protein), and telomerase.

Dendritic cell therapy: dendritic cells are isolated from patients and are loaded with tumor antigen peptides in vitro. These cells are injected into patients to boost anti-tumor T cell response.

• T cell therapy: patients’ T cells, activated in vitro with tumor antigens and cytokines (IL-12), are injected back to the patients.

Monoclonal antibodies for cancer therapyRituxan. Anti-CD20, a cell surface marker found on most B cells. Certain non-Hodgkins lymphomas.Herceptin. Anti-EFG-receptor-2 (also known as HER2, ErbB2 or Neu), which is overexpressed in ~25 percent of breast cancers. Erbitux, anti-EGFR (HER1), approved for metastatic colorectal cancerAvastin. Blocks the vascular endothelial growth factor (VEGF) receptor. An anti-angiogenesis drug.

Radiolabeled MAbsZevalin- A radiolabeled MAb to treat B cell non-Hodgkin lymphoma that has not responded to standard treatment. Bexxar - A radiolabeled MAb to treat certain types of non-Hodgkin lymphoma that no longer respond to rituximab (Rituxan) or chemotherapy. Radiolabeled antibodies approved by the FDA to detect cancer.OncoScint (for colorectal and ovarian cancer) ProstaScint (for prostate cancer).

Figure 12-49Immunization with MAGE-1/3 induces anti-melanoma immune response

Monoclonal antibodies to tumor antigens can deliver toxins or NK cells to tumor cells