Discovery of myeloid immune features predictive of response to cancer immunotherapy in prostate cancer

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy has been a revolutionary antitumor treatment and is approved to treat a plethora of cancer types. However, in solid tumors the response has been limited with only approximately 20 percent of patients responding except for patients with high tumor burden as evidenced by microsatellite instability (MSI) or mismatch repair deficiency (MMRD). The limited response is especially pronounced for prostate cancer. In prostate cancer, the only currently approved therapy (except for MSI/MMRD patients) is sipuleucel-T, a dendritic cell vaccine. Sipuleucel-T activates antigen presenting cells ex vivo before reinfusion where in vivo activation of B and T cell responses are associated with response to the therapy. This immunogenic myeloid and lymphoid cell interaction is just one example of a plethora of interactions which can be either immunogenic or tolerogenic. Improved understanding of the role of myeloid compartment in pro- or anti-tumor activity will allow for improved targeting of the myeloid compartment in combination immunotherapy strategies. Immunosuppressive myeloid states can be observed both in the periphery and in the tumor microenvironment. Peripheral monitoring of the immune system holds incredible potential due to the ease of monitoring and the ability for longitudinal repeated sampling. To characterize the heterogeneity of the circulating myeloid compartment, I used a genetic multiplexing strategy to simultaneously profile gene and protein expression on single cells from ~700,000 peripheral blood mononuclear cells (PBMCs) from longitudinal sampling of a metastatic castration resistant prostate cancer (mCRPC) cohort undergoing combined immunotherapy. In my first aim, I propose to use this dataset to describe novel myeloid cell states in the periphery and to investigate which states recapitulate in the tumor microenvironment and which states predict clinical response to the immunotherapy. In my second aim, I will investigate how these myeloid cell states interact with the lymphoid compartment to create an immunogenic or tolerogenic tumor response. My sponsor, Dr. Jimmie Ye, has extensive expertise in single cell –omics for profiling the immune system in both auto- immune and tumor contexts. My co-sponsor, Dr. Lawrence Fong, has made foundational discoveries in the field of cancer immunotherapy with a particular focused on the mechanisms behind response to cancer immunotherapy in genitourinary cancers, including prostate cancer. My co-sponsor, Dr. Matthew Spitzer, has extensive expertise in the understanding the systemic response of the immune system to a tumor with a particular focus in using mass cytometry for high dimensional single cell protein expression profiling. I will be undergoing longitudinal clinical training in cancer immunotherapy with Dr. Lawrence Fong, who is the director of the Cancer Immunotherapy Program at UCSF. Overall, this work will lay the foundation for improved prediction of response to cancer immunotherapy and the identification of novel targets within the myeloid target to improve clinical response in solid tumors.