Targeting Tumor-Intrinsic Immunosuppressive Mechanisms to Enhance Efficacy of Immune Checkpoint Blockade in Lung Cancer
Abstract
This proposal aims to dissect the mechanisms by which cancer cell specific IRE1-XBP1 signalinggenerates an immunosuppressive microenvironment that promotes tumor progression byinactivating cytotoxic T lymphocytes and simultaneously increasing immunosuppressive Tregs andMDSCs. Overcoming immunosuppression in the tumor microenvironment is a fundamental prerequisitefor the success of clinically relevant immune checkpoint inhibitors including anti-PD-1and CTLA4. We posit that treatment with IRE1 selective small molecule inhibitors will overcomemajor immunosuppressive barriers and boost anti-tumor immunity in NSCLC, which in turn mayconstitute a new approach in enhancing the efficacy of immune checkpoint inhibitors in NSCLC.This approach has the potential to increase the current objective response rates 17-20% withimmune checkpoint inhibitors in NSCLC. We expect that the mechanistic insights from theseinvestigations will generate unique translational opportunities that may lead to the design of futureclinical trials for currently untreatable mutant KRAS patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1119800
Entities
People
- Vivek Mittal
Organizations
- Weill Cornell Medicine