Boost to Immunotherapy by Switching Off Immunosuppression in Cancer, Crohn's and Alzheimer's

Highlights

• Scientists identify a molecular switch in an immune response against cancer that promotes their growth and proliferation.
• PI-3 kinase gamma suppression found to limit cancer growth
• The new discovery could improve cancer immunotherapy, and treatment of Crohn’s disease and Alzheimer’s.

Scientists have found a way to boost anti-cancer therapy by identifying a molecular switch which controls immune suppression in diseases like cancer, Crohn’s disease and Alzheimer’s. These researchers from The University of California San Diego hope that this discovery would improve immunotherapy treatment strategies. Dr. Judith A. Varner from The University of California San Diego’s Department of Pathology and Medicine said “Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective.We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”

Immune Suppression in Cancer

In normal human response to injury at a particular site in the body, macrophages are released, which in turn aid in the release of certain cytokines. These cytokines activate T- cells that attack the invading cells.

In the event of tumor, the following occur

• Tumor lesions or pre-malignant lesions are found to be infiltered with T-cells and other cells from an immune response.
• These tumor infiltering cells are part of the body’s defence mechanism against the tumor.
• These tumor infiltering immune cells are suppressed by the tumor
• Cytokines and growth factors that are secreted by these tumor infiltering cells aid in the growth of these tumor cells when their tumor disrupting activity is weak or absent.
• Further, cytokines that stop the healing process are also detected.

In diseases like Alzheimer’s and Crohn’s disease which lead to chronic inflammation, the cytokines and other cells mediated by an immune response affect normal cells.

PI-3 kinase Gamma (PI3Ky)

Dr. Varner and colleagues have found that an enzyme from macrophages PI-3 kinase gamma (PI3Ky) is found to suppress the immune response by blocking the activation of T cells that have anti-tumor activity.

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Blocking PI-3 kinase gamma (PI3Ky) in mice was found to

• Improved immune response to tumor.
• Suppressed the growth of tumors that were implanted into mice.
• Increased sensitivity of the tumors to anti-tumor drugs.

The cancer promoting activity of PI-3 kinase gamma (PI3Ky) validates previous studies that have shown that their intercellular disruption promotes the growth of cancer by a study conducted by Attoub S and colleagues and published in The Annals of The New York Academy of Science. According to this study titled “The transforming functions of PI3-kinase-gamma are linked to disruption of intercellular adhesion and promotion of cancer cell invasion”, in human colon epithelial cancer cells, the PI-3 kinase gamma (PI3Ky) lead to alterations in the homotypic cell-cell adhesion with the invasion of Type I collagen.

The current study by Dr. Varner and colleagues is aimed at the immune suppression ability of the PI-3 kinase gamma (PI3Ky) with the identification of a molecular mechanism that is involved in immune suppression which can be used to modulate immunotherapy.

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Moores Cancer Center’s Head of Cancer immunotherapy program, Dr. Ezra Cohen who is also the co-author of the study said “Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body’s own adaptive immune response. But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors. ”

In animal models of pancreatic ductal adenocarcinoma, the suppression of PI-3 kinase gamma (PI3Ky) in macrophages associated with tumor response inhibited

• Fibrotic scarring
• Metastasis
• Tumor cell invasion

When asked about the significance of identifying newer methods of treatment for cancers, especially pancreatic ductal carcinoma, assistant project scientist at Dr. Varner’s lab, Dr. Megan M. Kaneda said “PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed.”

Previous studies by these scientists on pancreatic ductal carcinoma involved the disruption of signals between B cells and macrophages that were tumor associated, this leads to

• Disruption in the tumor growth.
• Improved effectiveness of anti-cancer drugs.

This was carried out by the activation of Bruton tyrosine kinase which resulted in a natural immune response against tumor cells without any signs of suppression.

The growth and development of cancers have always been dependent on the body’s immune response,which has failed to control their multiplication. However, such studies throw light on molecular switches which may be activated to promote tumor growth. A reversal of this switch should, in theory, be able to restore normal function of the immune response which would aid in better control over tumor growth.

References:

1. Documentaion of Immune Suppression in Cancer Patients - (http://www.ncbi.nlm.nih.gov/books/NBK13517/)
2. Immune Suppression in Cancer - (http://www.aimath.org/WWN/tumorimmune/WhitesideImmuneSuppression.pdf)
3. Transforming Functions of PI3 Kinase-Gamma Linked to Disruption of Intercellular Adhesion and Promotion of Cancer Cell Invasion - (http://www.ncbi.nlm.nih.gov/pubmed/18837901)

Source-Medindia