Tumor Immunology

The increased incidence of cancer malignancies in patients with immune-deficiency diseases along with the detection of specific antibodies and T lymphocytes in patients with tumors prove the importance of the immune system in response to cancers¹. The normal immune response of the body that consists of natural killer T (NKT) cells, T cells, and NK cells is crucial to avoid cancer progression. These qualities indicate that tumor cells are immunogenic and express tumor-specific antigens², which allows them to be detected by the immune system. However, recent research suggests that tumor cells also have characteristics that allow them to evade the immune system; first, by proliferation aided by tumor-associated macrophages (TAM)³, and secondly by the down regulation of MHC receptors.

A tumor antigen activates the immune system through antibodies or specific cell recognition and is produced by tumor cells. Lymphocytes can recognize and initiate an antitumor attack on specific antigens and their epitopes. The CD8+ cytotoxic T cells recognize peptides that have been presented in the MHC I molecules of tumor cells. CD4+ T cells recognize slightly larger peptides secreted by tumor cells and presented by MHC II molecules (Figure 1). In the humoral immune response, tumor antigens are recognized by antibodies. The purpose of using both B cell and T cell immunology is to identify various tumor antigens. For example, in male patients with prostate cancer, there are elevated serum concentrations of prostate-specific antigens (PSA), which are expressed in very low quantities in men with healthy prostates⁴. There is potential in using tumor antigens to treat cancer patients, by either using medications to specifically target tumor specific antigens or by using them in tumor vaccines. Another use of tumor antigens is focused on the detection of cancer. For example, monoclonal antibodies are being used to detect breast cancer. In this specific case the antibodies target breast mucin, which is secreted by breast tumor cells⁵.

One way tumor cells can elude the immune system is by down-regulating MHC receptors, which evades cytotoxic T lymphocyte-mediated host immunity⁶. This down regulation would be caused by a mutated TAP gene, which leads to a deficient transporter associated with antigen processing (TAP1 and TAP2). Cancer immunotherapy aims to increase the expression of the lacking cytokines such as IFN-αβ and IFN-β, which will increase MHC Class I expression. This will induce a stronger antiproliferative response to tumor cells⁶.

Another way tumor cells evade the immune system is by the recruitment of nearby macrophages, which become tumor–associated macrophages (TAMs). TAMs facilitate the spreading of tumors by inducing tumor angiogenesis (Figure 2). Areas invaded by tumors produce factors such as MCP-1 (Monocyte chemotactic protein-1) and GM-CSF³. These factors are potent chemokines and continually recruit nearby monocytes into the tumor. Therefore, agents that antagonize the angiogenic factors secreted by TAMs would be effective in the inhibition of TAM-induced angiogenesis³. Recent research has focused on suppressing secretion of the angiogenic factors secreted by TAMs and blocking macrophage infiltration into the tumor mass as anti-cancer strategies.

References

¹Ghaffar, A, Nagarkatti, M. Tumor immunology. Microbiology and Immunology online. 2010. Available at http://pathmicro.med.sc.edu/ghaffar/tumor_immunol00.htm. Accessed March 18, 2011

²Bonertz A, Weitz P, Pietsch D, et al. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. Invest. 2009. Accessed March 20, 2011

³Chun-Chung, L., Ko-Jiunn, L., Tze-Sing, H. Tumor-Associated Macrophage: Its Role in Tumor Angiogenesis. Journal of Cancer Molecules, 135-140. 2010. Available at http://mupnet.com/jocm%202(4)%20135-140.pdf. Accessed March 21, 2011

⁴Frazer G. Identification of PSA as a novel tumor antigen associated with tumorigenesis of prostate cancer. Accessed March 20, 2011

⁵Hamid SS, Cheah SH. Generation and Characterization of a High-affinity Monoclonal Antibody for MUC1 Measurement in Breast Cancer. Hybridoma. 2011 2:137-43 Accessed May 3, 2011

⁶Yang, T. Mechanisms of MHC class I down-regulation in human cancer: accelerated degradation of tap-1 mRNA and disruption of TAP-1 protein function. 2009. Available at http://etd.ohiolink.edu/view.cgi/Yang%20Tianyu.pdf?osu1078192113. Accessed March 18, 2011

⁷Holland-Frei Cancer Medicine. 6th edition. Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Hamilton (ON): BC Decker; 2003. Accessed March 20, 2011

Clinical Application #1

Biomedical science is an evolving matter and immunology is no exception. Nowadays, scientists are putting efforts into the relatively new field of cancer vaccines. Cancer vaccines are designed to prevent infections by cancer-causing viruses, prevent the development of tumors in high risk-individuals and treat patients with existing cancer¹. The strategy for these vaccines is to target antigens on the surface of tumor cells that are recognized by both cytotoxic and T-helper cells. With that in mind tumors have been classified under two categories being tumor-specific shared antigens and tumor-specific unique antigens. Determining the specific antigens on the surface of the tumor is an essential part for the development of these vaccines in order to augment the immune response¹. When making the cancer vaccines, both antigen categories must be present in order to make the treatment the most specific and effective.

Under the cancer vaccine approach the method with the most promise is DNA vaccination. This method induces both humoral and cellular responses. In order to make this approach the most effective, two strategies have been implemented to make the vaccine extremely potent¹. First there is a physical delivery, which uses methods such as tattooing, gene gun, ultrasound, electroporation, and laser. The second approach is the non-physical delivery method also called viral and non-viral delivery systems which includes microparticles, target antigen-presenting cells

The most popular cancer vaccine known today is the human papillomavirus (HPV). This vaccine prevents HPV types 6, 11, 16, and 18, which may lead to cervical, vulvar, and vaginal cancers in women. A clinical trail done between December 2001 and May 2003 shows the results four years later of the initial vaccination. Results showed “vaccine efficacy against lesions related to the HPV types to be 96% for cervical intraepithelial neoplasia grade, 100% for both vulvar and vaginal intraepithelial neoplasia grade I, and 99% for condyloma” ². “Vaccine efficacy against any lesion in the generally naive population was 30%, 75% and 48% for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% for condyloma”². This demonstrated that after four years the vaccine still prevented against low-grade intraepithelial cancers. Researchers should use this as motivation to keep searching for other vaccines against cancer.

References

¹Bolhassani A, Safaiyan S, Rafati S. Improvement of different vaccine delivery systems for cancer therapy. Mol Cancer. 2011; 10: 3. http://url. Accessed March 21, 2011.

²Dillner J, Kjaer SK, Wheeler CM, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ. 2010; 341:c3493. http://url. Accessed March 21, 2011.

Clinical Application #2

The Tumor Microenvironment, Its Role in Tumor Progression, and How it Can be Manipulated to Promote Tumor Rejection

In 2009 the Cancer Immunology Working Group of AACR agreed that many mechanisms/cells such as regulatory cells, inhibitory ligands, and soluble factors like transforming growth factor-β operate in the tumor microenvironment. The type of dendritic cells in the tumor site also affects activation or tolerance of T lymphocytes. In a mouse Tramp model of prostate cancer, the presence of plasmacytoid dendritic cells proved to induce suppression of the tumor. Also, presenting CD4-positive cells into tumors changes the microenvironment and promotes immunity mediated by CD8-positive effector cells.

A correct T-cell activation by dentritic cells may occur by the inactivation of Treg function via the OX40 pathway. By administrating monoclonal antibodies to OX40, tumor rejection in mice models can be seen. The antitumor role of mast cells was established in mast cell-deficient mice, where it was demonstrated that mast cell’s infiltration into tumors caused significant inhibition of their growth. These newly described mechanisms, joined with strategies that block TGF-β and anti-CTLA-4 therapy can be appropriate for altering tumor microenvironment to benefit the host.

Results described new possible therapies that could affect “immune suppression” in the tumor environment. The number of CD3-positive T cells in the tumor inversely correlates with the vascular endothelial growth factor (VEGF) expression. In ovarian cancer, “55% of cases were shown to have CD3-positive infiltrating T cells, which was associated with long-term patient survival”¹. VEGF has immunosuppressive activity, and a decrease in its expression allows T-cell infiltration to occur, resulting in tumor rejection. Two novel genes have been identified within the vasculature of ovarian cancer, endothelin receptor A, which induces blood vessel constriction, and endothelin receptor B (ETRB), which induces vasodilation. ETRB expression was discovered to be increased in vascular cells within tumors showing low T-cell presence, the use of anti-ETRB blocking peptide (BQ-788) increases T-cell trafficking into tumors in a mouse model. Therefore, ETRB controls access of T cells into the tumor environment, and clinical trials will determine whether BQ-788 peptide shows efficacy by improving patient survival. It is clear that new clinical trials have to be done in order to test these new ideas in immunotherapy and help tumor prevention and treatment in the future.

Reference

¹McArdle S, Rees R. Tumor immunology: New Perspectives. Cancer Research. 2009;69. doi: 10.1158/0008-5472.CAN-09-0631

Clinical application #3

Immune manipulation can mediate the regression of established cancer in humans. For example researchers are using TAA, which are products on non-mutated genes encoding intracellular proteins commonly expressed by autologous cancer cells. The TAA are a new approach to treat patients with cancer and for the development of vaccination regimens with T cell epitopes.

According to Tiwari1 advanced tumor are generally not immunogenic because they do not express costimulatory molecules, however they can express TAA that can be recognized by T cells. For TAA to be effective depends on being phagocytosed and processed by dendritic cells. Because not only in preclinical models but also in humans, dendritic cells with high levels of HLA class I and class II are very efficient presenting TAA peptides in this way enhancing cellular immunity.

The way dendritic cells enhance cellular immunity is as follows: when they are immature they capture TAA in the peripheral tissues, process them into peptides bound to HLA molecules, and then migrate to lymphoid organs where they present HLA-peptide complexes to T lymphocytes. Following the interaction with TAA-specific T helper lymphocytes, dendritic cells become activated through the CD40 signaling pathway, up-regulate HLA and costimulatory molecules’ expression on their surface and acquire a mature phenotype, characterized by the expression of new markers such as CD83 and by the secretion of pro-inflammatory and chemotactic cytokines.

In the animal model, the researchers could link two different dendritic cell gene patterns with two levels of effectiveness in inducing tumor regression mediated by dendritic cell vaccine. Finally, if the researchers can confirm in a human model the results of the animal model, it might indicate new avenues in the design of more effective dendritic cell preparation protocols for antitumor vaccines because of the ability and specificity of dendritic cells to induce another cells in the body to attack cancer cells.

Reference

¹Tiwari M. From tumor immunology to cancer immunotherapy: miles to go. Journal of Cancer Research and Therapeutics. 2010;6(4):427-431

Questions

1. What are some of the ways a tumor interacts with the immune system?
2. What leads to the classification of a substance as a tumor antigen?
3. What are some potential anti-tumor immunotherapies?
4. A 36-year-old female patient came to the ER because of abdominal distention. She had these symptoms since last week and it has been getting worse. The patient is unremarkable for fever, diarrhea, nausea, and vomiting. Present history is remarkable for anorexia and loss of weight. She can't recall her last visit to her Ob/Gyn. Physical examination was positive for fluid wave, in the pelvic examination they found an anexal mass in the right lower pelvic region. Pelvic ultrasonography lecture came positive for a pelvic mass that covered the right ovary and fallopian duct. The patient is diagnosed with an ovarian fibroma. Which of the following is the most important cell in tumor angiogenesis?

a) Basophil

b) Eosinophil

c) Macrophage

d) Neutrophil

e) Mast Cell

5. A 56 years old female patient came with a chief complaint of fatigue and weakness. These symptoms started two weeks ago. The patient can't clean her house or go to work because she does not have enough strength. She presents history for anorexia, weight loss, low constant fever, poor skin color and "anal hemorrhoids". She can also remember pencil like stain in her stools. The patient had never visited a gastroenterologist. On the rectal exam they found hemorrhoid-like mass coming out from the anus. A biopsy was taken and resulted positive for anal cancer. CT scan was ordered and came positive for possible metastasis to the liver and lungs. The anal mass was extirpated and chemotherapy and radiotherapy were started. If an antigen is produced exclusively by a tumor cell, what would be its classification?

a) Tumor associated antigen

b) Tumor specific antigen

c) Epithelial antigen

d) Lymphocyte antigen

6. A 30-year-old male patient came to the dermatologist because of many genital warts. The physician explained to the patient that these warts are due to the Human papilloma virus. This virus is transmitted by sexual contact and can also cause none genital warts. There are different serotypes of this virus but 6, 11, 16, and 18 are the main one producing cervical and anal cancer. Also, these are the ones that vaccine created protection against. The physician tells the patient that it is too late to be vaccinated because he already has the disease but thinks he is a good candidate for Imiquimod. Imiquimod is a drug that stimulates the immune system inducing cytokine secretion creating an immune attack to the Human papilloma virus. In immunotherapy, what is the purpose of increasing the expression of IFN-alpha and IFN-beta?

a) Increase MHC class I expression

b) Decrease MHC class II expression

c) Initiate a humoral response

d) Activate complement

e) Downregulate TAP I

f) Upregulate TAP II