Research: Lung cancer is the leading cause of cancer death in the United States. The success of immune checkpoint blockade (ICB) with antibodies to PD-(L)1 have been a remarkable clinical advance. However, the majority of patients do not respond to ICB monotherapy and most of those who initially do respond eventually succumb to the disease. Malignant pleural effusions represent a challenging clinical scenario that is associated with poor prognosis and reduced responses to ICB. Preliminary data presented in this proposal demonstrates that activated T cells surprisingly express phosphatidylserine despite remaining viable and cytotoxic. Moreover, this expression of phosphatidylserine mediates susceptibility to phagocytic clearance by peritoneal macrophages that express the phosphatidylserine receptor Tim-4. In addition, Tim-4 abrogation improves responses to ICB in a murine model of peritoneal carcinomatosis. As pleural macrophages are ontogenically and transcriptionally similar to their peritoneal macrophage counterpart, we hypothesize that Tim-4+ pleural macrophages impart immunosuppression in malignant pleural effusions by clearing anti-tumor CD8+ T cells. In this proposal, we will systematically characterize Tim-4+ macrophage-PShigh T cell interactions in both murine and human models of malignant pleural effusion. Furthermore, we will explore whether Tim-4 blockade has the potential to substantially enhance the efficacy of immunotherapy in lung cancer. Candidate: Dr. Andrew Chow is a Medical Oncology Fellow in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSKCC).
He aims to become an independent, tenure-track physician-scientist investigating Tim-4+ pleural macrophages as a novel therapeutic target to overcome resistance to immunotherapies in lung cancer. Dr. Chow will conduct the proposed research under the mentorship of Drs. Charles Rudin and Jedd Wolchok, who are internationally recognized experts in lung cancer and immunotherapy, respectively. Dr. Chow has outlined a five-year period of mentored training that builds on his laboratory-based skills in mouse modeling, flow cytometry, and microscopy and his clinical training in medical oncology. For the next phase of mentored training, he will develop skills in single-cell RNA sequencing analysis, CAR T cell design and manufacture, CRISPR-Cas9 editing, and clinical protocol writing. Dr. Chow has also assembled a well- accomplished advisory committee composed of Drs. Sohrab Shah, Prasad Adusumilli, and Katherine Panageas, who will help to guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.
Understanding mechanisms of immunosuppression and identification of strategies to overcome resistance to immune checkpoint blockade and adoptive T cell therapies are critical to extend the benefit of immunotherapy to more patients. We have discovered that phagocytic clearance of phosphatidylserine-expressing viable CD8+ T cells by Tim-4 (phosphatidylserine receptor)-expressing macrophages mediates resistance to immune checkpoint blockade. The proposed research will systematically characterize these detrimental macrophage-T cell interactions in malignant pleural effusions and evaluate Tim-4 and phosphatidylserine abrogation as novel strategies for enhancing the efficacy of immunotherapy.
