2) Tumor Immunology

Briefly explain the approaches by which immunity against tumors be induced.

→ Immunity can be induced by immunizing subjects (such as mice or rats) with irradiated cancer cells

• surgical resection of a 1er tumor can cause the animal be be immune to subsequent challenges with the same tumor

What are the factors influencing tumor immunity?

1. Type of cancer (e.g., high to low immunogenic - UV > methylcholanthrene > spontaneous)

2. Method of its induction

What kind of immunization confers protective immunity against tumors?

prophylactic immunization (not therapeutic immunization)

• giving the vaccine before the pt get tumour (prophylactic)

How many days prior to challenge with live tumor cells is the prophylactic immunization initiated?

14 days & 7 days prior

Briefly describe specific immunity with an example.

→ immune response is unique to the individual tumor used for immunization

• e.g., mice immunized against a specific fibrosarcoma are immune only to that individual tumor line

• if challenged with a different fibrosarcoma, even one induced by the same carcinogen → tumor growth is unaffected

Name some common tumor types caused by Epstein Barr Virus.

1. Lymphoma

2. Burkitt’s lymphoma

3. Nasopharyngeal cancer

What is the influence of immunosuppression on development of tumors?

Immunosuppression → ↑ risk developing various cancers

Give 2 examples of tumor types found in Kidney transplant patients.

1. Kaposi’s sarcoma

2. Non-Hodgkin’s lymphoma

Name some common Hsp antigens and the type of cancer they are associated with.

Gp96: associated with fibrosarcoma, lung carcinoma, lymphoma, prostate carcinoma

Hsp70 & Hsp90: associated with fibrosarcoma & colon carcinoma

What are tumor specific antigens mainly made up of? What contributes to immunogenicity?

→ antigens belong to the family of HSPs

• specificity of immunogenicity is derived from the peptides chaperoned within the HSP's binding pocket rather than the HSP molecule itself

Identify the major families of tumor specific antigens.

• HSP90 (gp96 and HSP90)

• HSP70 (HSP110 and HSP/c70)

• HSP170 (grp170)

• Calreticulin

What do the HSP-chaperoned peptides contain?

→ have any tumor-specific antigenic epitopes present in the tumor cell

• act as the “antigenic fingerprint” of the tumor from which they were isolated

What happens when the peptides dissociate from HSP?

dissociation abrogates (ends) the tumor rejection activity

Outline the steps involved in the presentation of tumor specific antigens to APC’s.

1. HSP-peptide complexes bind to HSP receptors (like CD91) on APC

2. Complexes are endocytosed into the APC

3. Chaperoned peptides follow both the endogenous (Class I) and exogenous (Class II) pathways of antigen presentation

4. Peptides are processed and re-presented by MHC I & MHC II on the APC surface

5. HSP ligation induces upregulation of CD40 and CD80/85 + chemokines & cytokines production

What are the 2 types of MHC’s and T cells involved in recognition of tumor specific antigens?

1. MHC Class I - recognized by CD8+ CTLs

2. MHC Class II -recognized by CD4+ T cells

What are the main categories of tumor specific antigens?

1. HSP-peptide complexes

2. Cancer/testes (CT) antigens (e.g., MAGE, NY-ESO1)

3. Differentiation antigens (e.g., gp100)

4. Unique tumor-specific antigens (mutations)

5. Viral antigens

Name the 2 HPV antigens involved in development of cervical cancer.

1. E6

2. E7

Outline the steps involved in development of tumor immunity involving APCs and NK cells.

1. Tissue damage at the tumor site releases antigens and HSPs, which are taken up by APCs

2. APCs migrate to the draining lymph nodes and interact with naive T cells → clonal expansion of CD4 and CD8 T cells

3. NK cells play a crucial role in the response

4. Cytokines (IL-2, IFN-γ, IL-12) are needed for the effector functions of CD4, CD8 & NK cells

5. Effector cells enter circulation to reach the tumor site

What is concomitant immunity and its features?

→ phenomenon where a host with an already growing tumor is resistant to a 2^nd challenge of the same tumor

• tumor-specific

• eliciting a response that can eliminate a nascent tumor

• fails to eliminate the original tumor that elicited the response

What is the time frame during which concomitant immunity elicits protection? Why is the protection lost after this time frame?

• Narrow window of 7–10 days after tumor implantation

  • protection is lost after this time b/c a new population of suppressor T cells appears

Name the marker used for detection of Ovarian cancer, Leukemia, Hodgkin’s lymphoma.

Ovarian cancer: Ca 125

Leukemia: Common acute lymphoblastic leukemia antigen (CALLA) or CD25

Hodgkin’s lymphoma: CD30

Name the antigen involved and antibody used for Breast cancer, Colorectal cancer, Non-Hodgkin’s B cell lymphoma.

What are the major factors contributing to failure of tumor recognition?

• Inhibitory cytokines (TGF-β, IL-10)

• Inhibition of T cell activity via CTLA-4 & PD1

• Down-regulation through regulatory T cells

• Down-regulation of MHC Class I

• Generation of antigen-loss variants

• Loss of β2-microglobulin or components of the antigen processing machinery

How does CTLA-4 inhibit T cell?

By either

• raising the stimulatory threshold

• inhibiting the proliferative drive of the cells

What is the advantage of combining Anti-CTLA-4 antibody with a vaccine of irradiated melanoma cells?

(+) produces a significantly higher anti-tumor response than using anti-CTLA-4 antibody or vaccine alone

What is the influence of anti-CD25 antibodies on tumors?

Targeting CD25+ cells with these antibodies → robust T cell response and protective tumor immunity (even in aggressive models like B16 melanoma)

Name the antibody used against B cell lymphoma, colon cancer, breast cancer.

• B cell lymphoma: Rituximab

• Colon cancer: Cetuximab

• Breast cancer: Trastuzumab

Briefly explain the approach of HSP-peptide complex immunization used for cancer.

1. Tumor specimen is surgically excised from a patient

2. HSP-peptide complexes (like gp96 or hsp70) are purified from it

3. Purified complexes are vaccinated back into the same patient

   • has been shown to ↓ recurrence risk in some cancers (e.g., renal cell carcinoma)

What are the steps involved in adoptive immunotherapy using T cells?

1. Isolating tumor-infiltrating T cells from the pt

2. Expanding them in vitro

3. Infusing them back into the pt

What is the benefit of adoptive immunotherapy in melanoma pt?

dramatic tumor shrinkage

What are 2 types of primary tumors arise within the eye itself?

1. Retinoblastoma in children (under 5)

2. Melanoma in adults (60-65)

What are ways to treat eye tumors?

1. Laser treatment

2. Freezing (cryosurgery)

3. Surgical removal → reconstructive eye surgery with artificial eye implant

4. Radiation therapy