Elucidating the role of type 2 conventional dendritic cells in shaping anti-tumor immunity - Project Summary Immunotherapies that stimulate the immune system to kill tumors have revolutionized cancer treatment. Many immunotherapies in the clinic directly target cytotoxic CD8 T cells to reinvigorate their functional capacity and to kill tumors. However, such treatments have low objective response rates and therefore, it is imperative to utilize novel strategies that work synergistically to boost protection from these immunotherapies. Conventional dendritic cells (cDCs) are an ideal target as these antigen presenting cells play a critical role in regulating anti- tumor immunity by shaping the magnitude and character of anti-tumor T cell responses. cDCs are heterogenous and consist of two unique subsets, type 1 cDCs (cDC1) and type 2 cDCs (cDC2). cDC1s are well studied in cancer due to their ability to initiate and regulate CD8 T cell responses and correlate with increased responses to anti-PD-1 immune checkpoint blockade immunotherapy. The role for cDC2s in shaping anti-tumor immunity are less clear, but cDC2s have been associated with worse patient prognosis in metastatic melanoma patients. cDC2s are classically thought to regulate CD4 T cell responses, however, we and others have shown that cDC2s have the capacity to regulate CD8 T cell responses as well. Due to the availability of tools and their protective nature, cDC1s have been most studied in cancer. However, I have found that cDC2s induce unique CD8 T cell phenotypes in ex vivo studies and correlate with increased CD8 T cell exhaustion in metastatic melanoma. In this project, I will test the hypothesis that intratumoral cDC2s limit anti-tumor immunity by promoting CD8 T cell exhaustion. I will test this by utilizing ex vivo co-cultures to understand the mechanisms by which cDC1s and cDC2s differentially regulate CD8 T cell phenotype (Aim 1) and by characterizing the co-localization of cDC subsets and exhausted CD8 T cells in human melanoma with spatial transcriptomics and fluorescent multiplex immunohistochemistry (Aim 2). The proposed research will address major knowledge gaps regarding how different cDC subsets regulate anti-tumor CD8 T cells within the tumor microenvironment and will contribute to the development of novel immunotherapies that will work in concert with current treatment options to boost anti-tumor immunity.
