Tumor Immunology Flashcards
Tumor Specific Antigens
1) Mutated Proteins with no role in malignant transformation.
2) Mutated Proteins involved in malignant transformation:
- -Oncogenes
- -Suppressor genes
3) Normal Proteins that are Overexpressed or Aberrantly Expressed:
- -Embryonic proteins
4) Viral Proteins in Tumors caused by Oncogenic Viruses (e.g. HPV)
Role of CD8+ CTLs in Immune Response Against Tumors
CD8+ CTLs are the major mediators of immune response against tumors.
*Requires Cross-Presentation:
–Tumor cells do not produce Costimulators and Don’t express Class 2 MHC.
–Therefore, Tumor cells cannot activate Naive CD8+ or Naive CD4+ T cells on their own.
–CTL responses to Tumor cells depends on processing by APCs (Dendritic cells or Macrophages).
**Processed Tumor Antigen is presented by APC Class 1 MHC to CD8+ T cells and Class 2 MHC to CD4+ T cells, along with Costimulators.
Role of CD4+ T cells and B cells
Anti-Tumor CD4+ T cells may help expand Anti-Tumor CTLs and also Anti-Tumor B cell responses.
Some tumor specific antibodies have been detected in cancer patients. (but little evidence that this is protective)
Role of Macrophages and NK cells
Experimental studies have shown that *Macrophages and *NK cells can kill Tumor cells “In Vitro.”
NK cells recognize Cell Stress and Downregulation of Class 1 MHC on Cancer cells.
Tumor Evasion of Immune Responses
1) Immune Responses against tumors may be very Weak because *Many Tumor Antigen are only slightly different from normal protein and therefore are Weakly Immunogenic.
2) Tumors may develop mechanisms of evading immune responses:
- -Antigen Loss
- -Down Regulation of Class 1 MHC
- -*Production of Immunosuppressive Cytokines, such as *TGF-Beta
Immunotherapy
*Goal of Immunotherapy is to Specifically Target Tumor cells,
- -Without damaging the normal host cells.
- -Chemotherapy and radiation therapy, in contrast, still damage normal host cells.
Ideally, Anti-Tumor Immune response should seek tumor cells, regardless of their Location.
–This would avoid the issue of surgery, where success is measured by the ability to dissect around tumor to remove it all, which depends on tumor size, borders, and location.
3 Main Approaches:
1) Give patient *Anti-Tumor Effector Antibodies or CTLs
2) *Actively Immune Patients against their own tumors
3) *Stimulate patient’s own Anti-Tumor immune response
Antibodies Against Tumor
*Monoclonal Antibodies to various Tumor Antigen, *Coupled with a Potent Toxin.
(not very successful yet)
CTL Adoptive Immunotherapy
1) Isolate T cells from blood or Tumor bed (Tumor infiltrating lymphocytes)
2) Expand T cells in culture by IL-2
3) Transfer T cells back into patient with or without systemic IL-2: Adoptive Immunotherapy
4) Tumor Regression occurs
(has been able to shrink tumors, but never completely killed the tumors)
Tumor Vaccines
Many new approaches rely on *Boosting the Host’s Natural Immune Responses with **Tumor Vaccines.
–Patients could be vaccinated with their own tumor cells, purified Antigen from their own tumor cells, or even recombinant tumor antigen administered with adjuvants.
In one new approach:
*Dendritic cells are isolated, *Cultured, and *Expanded with GF and *Exposed to Tumor
= *Tumor-Pulsed Dendritic Vaccines
–>Dendritic cells bearing Tumor antigen mimic Cross-presentation and generate CTLs against tumor.
In another approach:
*Plasmid with Tumor Antigen cDNA is Transfected in Host cells, such as *Dendritic cells.
–> Production of Antigen by Dendritic cells *Generates CTLs Against Tumor cells expressing Tumor Antigen.
Another approach:
*Tumor cells are *Transfected with *Costimulators, such as B7.
Cytokine Therapy
Let patients develop their own tumor specific immune responses and optimize them with cytokines:
*IL-2: Causes *Vascular Leak with *Pulmonary Edema and Shock.
(Limited success with melanoma and renal carcinoma)
*TNF: *Causes Complications Resembling Septic Shock. (Isolated limb perfusion for melanoma)
*IL6: *Causes Liver and CNS Toxicity.
(used in renal cell carcinoma)
