The Effect of Tumor Burden on Peripheral cDC1 Activation and Functionality

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PROJECT SUMMARY/ABSTRACT Tumors disrupt the homeostasis of the immune system, altering immune cell composition and phenotype in the tumor microenvironment (TME), lymph nodes, spleen, blood, and bone marrow. Mounting a de novo immune response both peripherally and intratumorally is required for tumor clearance. Conventional type I dendritic cells (cDC1s) are a critical component of this response and in the success of many immunotherapies. Tumors are known to impair the function of cDCs in the TME, but questions about peripheral cDCs remain: how do immunosuppressive mechanisms of tumors extend to cDCs in the spleen? In what ways do these immunosuppressive pathways affect the CD8 T cell priming abilities of cDC1s? Answering these questions will advance our understanding of cDC biology, tumor pathogenesis, and better inform effective immunotherapy development. This proposal will test the hypothesis that soluble factors in the periphery of tumor-burdened hosts alter the ability of cDC1s to prime de novo CD8 T cell responses to secondary infection. Aim 1 of this proposal will determine the upstream mediators of impaired splenic cDC1 activation with tumor burden. Aim 2 will determine the mechanism of defective CD8 T cell priming by splenic cDC1s in the context of tumor burden. This research approach will be carried out using a variety of methods including single-cell proteomic analysis (flow cytometry and Mass Cytometry by Time of Flight (CyTOF)), imaging studies, ex vivo co-cultures, and in vivo assays. These proposed studies will be some of the first mechanistic studies to assess ways that tumor burden can alter peripheral cDC functionality. This could result in the novel discovery of pathways important in the adaptive immune response to blood borne infections and result in furthering our understanding of dendritic cell and T cell interactions. Translationally, this work will improve our understanding of cancer patients’ susceptibility to infections and reveal potential therapeutic interventions. Further, this work will better inform immunotherapy approaches for cancer treatment itself, especially in the adoptive cell therapy field – specifically, how dendritic cell vaccines derived from peripheral cells or adoptive T cell therapy can be further improved. This research project and fellowship training will be conducted at a top-funded research institution, the University of California, San Francisco (UCSF), in the laboratories of Dr. Matthew Spitzer and Dr. Lewis Lanier. Dr. Lanier has made extensive foundational discoveries in immune cell biology over the course of his career. Dr. Spitzer is an investigator with expertise in systems cancer immunology approaches and dendritic cell biology. These mentors and institution will provide a rich training environment for completion of the proposed research and development of professional skills necessary for a continued academic research career.