Systematically Investigate Anti-Cancer Drug’s Modulation on T Cells in Tumor Microenvironment

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

SUMMARY: Despite the transformative impact of immune checkpoint blockade (ICB) therapies in cancer treatment, the persistent challenge of low response rate and high risk of ICB resistance necessitates innovative approaches. Emerging studies acknowledge the immunomodulatory effects of conventional chemotherapies and small molecule inhibitors. However, due to the limited insight of interactions between drug treatment and tumor microenvironment, the synergy potential of most anti-cancer drugs with immunotherapy are not systematically evaluated. In our recent publication, we proposed a novel chemo-immunotherapy synergism prediction algorithm based on the post-treatment transcriptomic profiling of tumor cells and cancer patients. In this proposal, we seek to expand our approach to exploring the chemo-immunotherapy synergisms specifically through the lens of immune cell populations within tumor microenvironment. By comprehensively profiling pharmacologically or genetically perturbed T cells and analyzing their interactions with tumor cells, we seek to identify novel drug combinations that can overcome ICB resistance by modulating T cell activities. To achieve this goal, we have designed three specific aims: AIM I (K99) will conduct in silico screening of anti-cancer drugs that can impact T cell effector function, activation, stemness and proliferation; AIM II (K99-R00) will conduct single-cell CRISPR KO (scCRISPR-KO) screening of anti-cancer drug targets that can regulate T cell anti-tumor immunity; based on the Perturbed T Cell Signature Compendium (PerTCellS) built upon AIM I and II, AIM III (R00) will construct a T cell-centric ICB response signature and develop a novel synergy prediction algorithm to identify anti-cancer drugs that can boost ICB therapy through priming T cells. Our approach will provide a novel and comprehensive insight of interactions between anti-cancer drugs and T cell functionalities, which will facilitate the discovery and the repurposing of chemotherapy agents and small molecular inhibitors to enhance immunotherapy efficacy.