Rajesh K. Sharma
University of Louisville, USA
Title: Chemokine receptors in cytotoxic T-lymphocyte trafficking to tumors: Implications for immunotherapy
Biography
Biography: Rajesh K. Sharma
Abstract
Cancer immunotherapy has recently emerged as a viable alternative to standard of care therapies and many FDA approved immunotherapies are in clinic. Several new forms of immunotherapies targeting cytotoxic-T-lymphocytes (CTLs) such as adoptive cell therapies and vaccines are in advanced clinical trials. In all of these, trafficking of CTLs to tumor is a critical step for achieving therapeutic efficacy. However, inefficient infiltration of activated CTLs into tumors is increasingly being recognized as one of the major hurdles limiting efficacy. We herein investigated the roles of chemokine receptors in regulation of CTL migration to tumor. Using tumor studies in receptor knockout mice, depletion of CTLs, adoptive transfer in Rag2-/- mice, we have demonstrated the critical role of BLT1 in controlling the migration of CTLs to tumor in cervical cancer model. Furthermore B16 melanoma model was used for validation of this notion and evaluation of the involvement of another chemokine receptor CXCR3 that has been widely implicated in migration of CTLs in context of infection or autoimmunity. We herein demonstrate that BLT1 and CXCR3 both receptor play a critical and combinatorial role in controling the CTL traficking to tumor. We finally showed that anti-PD-1 antibody immunotherapy failed in BLT1-/- and CXCR3-/- mice suggesting the indisapansable requirement of these receptor during therapy. These studies provides further insights in CTL migration to tumor during tumor development as well as the course of cancer immunotherapies. The findings may have translational implications for improving inharent as well as immunotherapy induced CTL responses in cancer patients.