Role of the Inhibitory Receptor TIGIT in the Regulation of CD4+ Tregs in Patients With Advanced Melanoma
Abstract
There is ample evidence that melanoma express antigens recognized by cytotoxic T lymphocytes (CTLs). However, these T cells most often fail to induce tumor rejection in humans. Therefore, a better understanding of the mechanisms governing the resistance of advanced-stage melanomas to anti-tumor T cell immune responses is critical to develop a potent therapy of melanoma. One of the major mechanisms used by melanoma to dampen antitumor CTL responses is the recruitment at tumor sites of regulatory CD4+ T cells (Tregs). Increased numbers of CD4+ Tregs and decreased numbers of CTLs at tumor sites are correlated with poor prognosis in various types of cancers, including melanoma. It is therefore expected that immunotherapeutic strategies aimed at depleting Tregs and/or reversing their inhibitory functions at tumor sites will improve immune responses against melanoma. This proposal is based on the hypothesis that a number of immune checkpoint inhibitory receptors expressed by CTLs and also that CD4+ Tregs play a role in mediating melanoma-induced Treg immunosuppression and may be targeted by monoclonal antibodies (mAbs) to enhance T cell responses to melanoma and increase the likelihood of clinical benefits in patients with advanced melanoma. In particular, this research proposal will focus specifically on a newly described T cell inhibitory receptor named TIGIT (T cell Immunoreceptor with Ig and ITIM domains). TIGIT appears to be upregulated by CD4+ Tregs present in peripheral blood of healthy donors, and Tregs that express TIGIT have been shown to exhibit superior suppressive capacities. However, it is unknown whether TIGIT is upregulated by CD4+ Tregs at periphery and at tumor sites and whether TIGIT plays a role in promoting Treg-induced immunosuppression in patients with advanced melanoma. Based on a series of preliminary observations listed in this application, we propose to investigate in blood and at tumor sites of patients with advanced melanoma whether: (1) TIGIT is expressed by CD4+ Tregs; (2) TIGIT+ CD4+ T cell exhibit high immunosuppressive functions; and (3) targeting TIGIT on Tregs with anti-TIGIT mAbs can reverse Treg-induced immunosuppression and/or deplete the population of TIGIT+ Tregs in blood and at tumor sites of patients. We expect that targeting TIGIT+ Tregs will improve antitumor immune responses and increase the likelihood of clinical benefits for patients with advanced melanoma. Julien Fourcade, PharmD, PhD, Principal Investigator of this project, has expertise in the field of human cancer immunology and he is actively investigating the mechanisms of tumor-induced immunosuppression in patients with advanced melanoma at the University of Pittsburgh Cancer Institute (UPCI). He has independently developed this proposal and generated the preliminary data. This Peer Reviewed Cancer Research Program (PRCRP)-funded research grant will be critical to support Dr. Fourcade s research efforts aimed at finding more effective treatments for melanoma. Dr. Fourcade s career development plan, which includes weekly laboratory and one-on-one meetings with his Mentor, the participation in weekly seminar series of the UPCI and the Department of Immunology, monthly Cancer Immunology Program meetings and attendance at annual local, national, and international scientific meetings, will provide Dr. Fourcade with the opportunity to increase his knowledge in the field of melanoma research and to successfully develop into an independent investigator. The findings in this proposal will support the development of clinical grade anti-TIGIT mAbs for future evaluation in the clinic. Therefore, the proposed research may be potentially beneficial not only to patients with advanced melanoma but also to patients with other types of solid tumors. The findings in this application will also advance our understanding of the molecular mechanisms used by CD4+ Tregs to impede antitumor immune responses and tumor rejection in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510510
Entities
People
- Julien Fourcade
Organizations
- United States Army
- University of Pittsburgh