528 Use of a novel antibody labeling method to track leukocyte migration into tumors following PD-1 immunotherapy

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Background Immunotherapy is a potent weapon against cancer, with inhibitors of the PD-1/PD-L1 pathway through immune checkpoint inhibition (ICI) being the most effective. Though a subset of patients can achieve a durable response, a majority experience disease progression, highlighting the need to better understand the mechanisms driving response. Recent studies have implicated the tumor draining lymph node (TDLN) as reservoir of CD8+ T cells that are more functional than the T cells in the tumor, however a better understanding of how PD-1 inhibitors drive recruitment of these T cells to the tumor, as well as the function and influence of these recently recruited CD8+ T cells on other immune cells in the tumor is needed. Methods To shed light on the recruitment dynamics of immune cells we have adapted an intravenous antibody-based labeling technique to track immune cells that have migrated into the tumor. This method labels cells in the vasculature and is cell-associated for up to 72 hours, enabling detection of cells that migrated from the blood into the tumor within that time window using flow cytometry or immunofluorescence imaging. Results In subcutaneous MC38 tumors at early stage of disease, we found that PD-1 blockade significantly increased the infiltration of cytotoxic Granzyme B+ CD8+ T cells in the 72 hour labeling window compared to isotype treated tumors. Furthermore, we observed differences in myeloid cell recruitment between treatment groups, with more macrophages and monocytes infiltrating 72 hours before harvest in isotype treated tumors. Further characterization of these myeloid cells revealed recently recruited macrophage/monocytes in the anti-PD1 treatment group have increased expression of the inflammatory marker iNOS, and decreased expression of immunosuppressive markers Arginase and CD206 compared to isotype control. Conclusions These early results demonstrate that PD-1 blockade increases recruitment of inflammatory myeloid subsets along with cytotoxic CD8+ T cells from the periphery, which helps create a more immunostimulatory tumor microenvironment. Our work highlights the potential of the novel antibody IV labeling method to identify and phenotype recently recruited immune cells to the TME, and provides a more precise temporal resolution of leukocyte migration to the tumor following PD-1 blockade. Ethics Approval All animal work on this study was approved by the IACUC at the University of Texas MD Anderson Cancer Center; approval number 00002324-RN00.

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