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Research: Boosting Subdominant Cancer-Specific T Cells

Dr. Mansour Haeryfar, Associate Professor of the Departments of Microbiology and Immunology and Medicine, and his team at Schulich Medicine & Dentistry have uncovered a new mechanism underlying the beneficial effects of PD-1-based “checkpoint inhibitor”, therapeutic agents that are approved for the treatment of several types of cancer and also under investigation in clinical trials for numerus other types.

Haeryfar and his team revealed that blocking programmed death-1 (PD-1), a cell surface protein found on exhausted anticancer T cells, provides the immune system with more tumor targets to go after. This study was published and also highlighted in the November edition of The Journal of Immunology, the flagship journal of the American Association of Immunologists.

 Dr. Haeryfar explains the significance of this work:

 “Killer T lymphocytes are often present in cancer patients or even inside their tumor masses; yet, they typically fail to eradicate cancer. Previous studies have demonstrated that sustained interactions between T cells and tumor cells, especially when dealing with a high tumor burden, results in T cell exhaustion. This phenomenon has been attributed to the inhibitory function of PD-1. As such, anti-PD-1 antibodies have been used to reinvigorate tumor-specific killer T cells in both preclinical studies and clinical trials. Such trials have met with success in several malignancies. However, not all cancer types or patients are equally responsive to such antibodies, and our understanding of how PD-1-based therapies (which are often referred to as “checkpoint inhibitors”) work is far from clear.

Many studies to date have focused on the effects of anti-PD-1 antibodies on the response magnitude of so-called immunodominant T cells. These T cells respond to tumor antigens more rigorously than other T cell clones, dubbed as subdominant T cells. The above experimental approach is technically convenient and still valid. However, it ignores the fact that immunodominant T cells are “more visible” to the immune system and more likely to be tolarized as a result, to the patient’s detriment. In our recent study utilizing a clinically relevant mouse model, we investigated the effect of an anti-PD-1 antibody on both immunodominant and subdominant anticancer T cell responses. Much to our surprise, we found that PD-1 blockade selectively boosted several important functions of subdominant T cells.

Mechanistically, we discovered that blocking PD-1 prevents immunodominant T cells to compete with and lyse subdominant T cells. Therefore, interfering with PD-1’s action prolongs the survival of subdominant T cells, which may sometimes be more protective against cancer. Also importantly, this immune-enhancing effect was not exerted at the expense of immunodominant responses. Therefore, my team has demonstrated, for the first time to my knowledge, that blocking PD-1 allows the immune system to efficiently target more tumor antigens. This has obvious implications for cancer immunotherapy and for antitumor vaccine design.”