Macrophages as modulators of T cell function and therapeutic response in clear cell renal cell carcinoma - PROJECT SUMMARY/ABSTRACT The treatment of metastatic clear cell renal cell carcinoma (ccRCC), the most common and lethal form of renal cell carcinoma, has been revolutionized by therapies directed at vascular endothelial growth factor (VEGF) and immune checkpoint blockade (ICB) therapies. Despite this progress, the majority of patients with advanced disease will develop treatment resistance and ultimately succumb to their disease, making alternative therapeutic strategies a critical need. We have previously demonstrated that ccRCC is highly immune infiltrated, mostly by T cells and antigen-presenting cells (APCs), in particular, tumor-associated macrophages (TAMs). We and others have further demonstrated that TAMs are associated with resistance to both ICB and VEGF-directed therapy, a process thought to be mediated, in part, by T cell exhaustion. However, TAMs are phenotypically and functionally diverse, and our preliminary evidence suggests that only some TAM subpopulations are associated with therapeutic resistance. We hypothesize that specific TAM subpopulations can impact tumor control and response to therapy by presenting antigen to and influencing T cell phenotype, and therefore that specific inhibition of these TAMs may increase response to the therapies. To test these ideas, we propose first to finely characterize APC populations in 3 unique sets of human tumors: treatment-naïve, responsive to combination therapy, and resistant to the therapy. We then assess APC populations as predictors of patient outcome to construct new predictive models. Next, to uncover how antigen presentation by TAMs locally modulates anti-tumor T cell responses, we will use a novel genetically faithful, immunocompetent murine model. Specifically, we will assess immune cell phenotypes and tumor growth in mosaic mice with TAM-specific genetic ablation of antigen presentation function, as well as assessing TAMs in vitro for ability to present antigen and influence T cell states. Finally, we will take advantage of indications that various macrophage-directed drugs in clinical development may selectively inhibit different TAM subsets. After determining which TAM subpopulations are associated to resistance to current therapies for ccRCC (anti-PD-1, anti-PD-L1, and the VEGF receptor inhibitor cabozantinib), we will use the mouse model to assess whether resistance can be overcome by treating with a macrophage-directed drug that inhibits the resistance-associated TAM subsets. In summary, the proposed research will yield a detailed atlas of APC and T cell states in ccRCC, a novel model to predict patient outcome, and an understanding of the role of antigen presentation by TAMs in ccRCC. Further, the proposed research may reveal a means of overcoming resistance to widely used therapies for ccRCC. Therefore, this work can open the door for precision-based TAM inhibition strategies to overcome treatment resistance in ccRCC and other immune infiltrated tumors.
