Abstract 2100: Dendritic cell-intrinsic PTPN22 negatively regulates anti-tumor immunity

Abstract

Abstract Checkpoint blockade immunotherapies have revolutionized cancer treatment; however, only a subset of patients benefit. Individuals with a loss-of-function single nucleotide polymorphism (SNP) in the gene encoding tyrosine-protein phosphatase non-receptor type 22 (PTPN22) are at increased risk for autoimmune disease and display a lower incidence of certain cancers. Studies in PTPN22 knockout (KO) mice have established it as a negative regulator of T cell responses in autoimmune and cancer models attributed to a hyperactive T cell response. However, these studies have not defined the cell lineage-intrinsic roles of PTPNN22 in distinct immune cell compartments, and the potential role of PTPN22 in myeloid cells remains undefined. Myeloid cells in general, and dendritic cells specifically, are critical modulators of antitumor T cell responses. We have developed a novel dendritic cell (DC) PTPN22 conditional KO (cKO) mouse model that enables deletion in CD11c+ cells. Deletion of PTPN22 in DCs resulted in augmented tumor control, evidenced by a significant reduction in tumor burden at endpoint. We found that at end point total CD8+ T cells, but not CD4+ T cells or Tregs, were increased in the tumors of CD11c+ PTPN22 cKO mice compared to control mice. The use of the syngeneic murine melanoma cell line B16.F10 expressing the model antigen “SIY” (B16.SIY) allowed for the tracking of endogenous tumor antigen-specific T cell responses. Indeed, CD8+ T cells demonstrated increased expression of both activation and memory markers at day 10 in the tumor draining lymph node (tdLN) and in day 27 tumor infiltrating lymphocytes. Depletion of CD8+ T cells with an anti-CD8β monoclonal antibody eliminated the tumor growth control in this model, suggesting a mechanism of action based on the DC-CD8+ T cell axis. To test precisely for increased antigen-specific T cell priming, we utilized IFN-γ ELISpot analysis on the tdLN and spleen of tumor bearing mice. We found an increased frequency of IFN-γ-producing T cells in the presence of tumor antigen SIY, but not irrelevant control antigen SIINFKL. Spectral analysis of tumor antigen-specific T cells in the tdLN at the same timepoint showed a significant increase in the number and percentage of CD8+ SIY+ T cells displaying elevated activation and memory markers. Lastly, analysis of DCs in the tdLN similarly revealed an increase in the quantity and percentage of DCs attributed to an increase of CD103+ DCs, but not CD11b+ DCs, displaying increased activation and proliferation markers. Thus, we show that deletion of PTPN22 in DCs is sufficient to drive a tumor antigen-specific T cell response resulting in enhanced tumor control. This work highlights the potential to modulate anti-tumor immunity through the manipulation of DCs. Citation Format: Santiago Acero-Bedoya, Emily F. Higgs, Thomas F. Gajewski. Dendritic cell-intrinsic PTPN22 negatively regulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2100.