The advent of novel immunotherapies has underscored the critical importance of the T-cell response to both the endogenous and the therapeutically-driven anti-tumor immune response. We have found that the tumor infiltration of CD8 T-cells in renal cell carcinoma (RCC) is widely variable (>10,000 fold) and that patients with increased CD8 T-cell infiltration experience increased cancer-specific survival. In seeking to understand the biology which controls T-cell infiltration into tumors, we found and defined a stem-like CD8 T-cell population that is the reservoir of effector cells in human cancers, including RCC. This stem-like CD8 T-cell population maintains the anti-tumor T-cell response by self-renewal and differentiation into new effector cells. Importantly, when the stem cell is lost, there can be no prolonged immune response. Highly T-cell infiltrated tumors are similarly infiltrated by antigen presenting cells (APCs), and stem-like CD8 T-cells aggregate in these APC-dense zones. When this APC niche is lost, the T-cell response to the cancer fails, and we hypothesize that an APC niche is required to support stem-like CD8 T cells in tumors. The work proposed here will investigate the mechanisms that underlie these findings, which may ultimately lead to enhanced therapeutic approaches to treating RCC. Our overarching hypothesis is that that T-cells and dendritic cells self-aggregate, creating a lymphoid-like microenvironment in the tumor which supports stem-like CD8 T-cells in the tumor. In this proposal, I will investigate the APC subsets infiltrating human RCC tumors and test the role of specific chemokine signals in the aggregation of T-cells with these APCs.
In Aim 1, I will test the hypothesis that the chemokine XCL1 in the tumor microenvironment assists the aggregation and organization of stem-like CD8 T-cells and XCR1+ CD141+ cross presenting dendritic cells, allowing for the continued production of new effector-like CD8 T-cells in the tumor by (a) investigating the co-localization and activating properties of XCR1+ DCs on TCF1+ CD8 T-cells and (b) determining the role of XCL1 in the migration of XCR1+ DCs isolated from human RCC tumors. Furthermore, as immunologically relevant murine models are needed to investigate the mechanisms behind observations made in primary human cancer samples, in Aim 2, I will (a) establish and rigorously validate a model of murine RCC that can be used to study the anti-tumor immune response in an antigen specific manor and use this model to (b) test the hypothesis that XCL1 produced by intratumoral T-cells incites XCR1+ DC migration and results in the formation of intratumoral immune aggregates. Together, these aims will provide fundamental understanding of the mechanisms which permit T-cell infiltration and lymphoid aggregation in tumors, uncovering why some tumors have significant T-cell infiltration, while others do not. Gaining this understanding will fulfill the long-term goal of this research: to apprise the biology responsible for the utility of T-cell based immunotherapies and to unearth new strategies for clinically exploiting the anti-tumor immune response.

Public Health Relevance

Immunotherapy?a treatment strategy which leverages the power of the body's immune system against cancer? is one of most promising approaches available to treat human cancer, yet clinical response rates, particularly in renal cell carcinoma, fail to exceed 20-30%. Thus, a more robust understanding of the mechanisms of the body's immune response to cancer is essential for improving cancer treatment and care. Through providing critical insight into the body's immune response to cancer?specifically in context of renal cell carcinoma?this study will generate knowledge that can be directly applied to improve patient care.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Bian, Yansong
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Emory University
Schools of Medicine
United States
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