Previously Funded Research

Chendi Li, PhD

Massachusetts General Hospital

Research Project:

Enhancing anti-tumor chemokines in KRAS G12C inhibitor-resistant non-small cell lung cancer

Summary:

Over the past few years, treatment options for patients who have KRAS-mutated lung cancer have expanded to include immunotherapies and targeted KRAS inhibitors. These agents, while effective in some patients, do not induce deep or durable responses in the majority of patients. This has prompted clinical trials combining KRAS inhibitors with immunotherapies. Early results look promising, with response rates greater than either agent alone. However, 25–40% of patients still do not respond to the combination. Thus there remains an urgent need to understand why these treatments fail in order to develop new strategies with enhanced efficacy to benefit a greater number of patients.

Accumulating evidence suggests that KRAS inhibitors induce changes in tumor cells that make them more immunogenic, thereby increasing the effectiveness of immunotherapies. Dr. Li and others have observed that KRAS inhibitors induce expression of genes related to interferon signaling, including cytokines and chemokines that attract immune cells such as T cells into tumors. Preliminary studies suggest that this drug-induced expression of chemokines in lung cancer cells treated with KRASG12C inhibitors is not uniform, either between different tumors as well as between different cancer cells within the same tumor. Moreover, preliminary data suggests that this difference may result from the way cancer cells regulate a key transcription factor responsible for interferon signaling called IRF1.

Dr. Li hypothesizes that targeting these co-regulators of IRF1 may provide a means for boosting the production of chemokines that are necessary for recruit anti-tumor T cells into the tumor, thereby increasing the efficacy of anti-PD-1 immunotherapies. In this project, her team aims to first to define the role of candidate transcription factors and co-regulators of IRF1 identified by their preliminary data in regulating chemokine expression induced by KRAS inhibitors. They will genetically engineer patient-derived KRAS-mutant lung cancer cell lines to suppress or increase these factors and assess the effects on chemokine production. They will also use patient-derived xenograft (PDX) mouse models of KRAS-mutant lung cancers to study how KRAS G12C inhibitors induce chemokine production within tumor cells in vivo.

Second, Dr. Li’s team will evaluate whether the chemokines induced by KRAS-targeted therapy can attract immune cells to tumor cells. They will use a microfluidic co-culture system to study human tumor organoids that incorporate T cells and the tumor immune microenvironment, allowing us to model immune cell recruitment in a controlled ex vivo setting. This approach will help establish proof-of-concept evidence supporting the potential for KRAS G12C–induced C-X-C motif chemokine ligands (CXCLs) to reverse an immunosuppressive tumor microenvironment.

Altogether, this proposal seeks to understand mechanisms underlying the failure of some tumors to respond to combined KRAS and PD-L1/PD-1 inhibition. By identifying the transcriptional regulators of chemokines that recruit T cells and turn immune “cold” tumors “hot,” this work will provide a foundation for future efforts to design therapeutic strategies to promote immune cell infiltration.