CD4 + T cells play a critical role in anti-tumor immunity via recognition of peptide antigens presented on MHC class II (MHC-II). Although some solid cancers can be induced to express MHC-II, the extent to which this enables direct recognition by tumor-specific CD4 + T cells is unclear. We isolated and characterized T cell antigen receptors (TCRs) from naturally primed CD4 + T cells specific for two oncoproteins, HPV16 E6 and the activating KRAS G12V mutation, from head and neck squamous cell carcinoma (HNSCC) and pancreatic ductal adenocarcinoma (PDAC) patients, respectively, and determined their ability to recognize autologous or human leukocyte antigen (HLA)-matched antigenexpressing tumor cells. We find in both cases that the TCRs are capable of recognizing peptideloaded target cells expressing the relevant MHC-II or B cell antigen-presenting cells (APC) when the antigens are endogenously expressed and directed to the endosomal pathway but fail to recognize tumor cells expressing the source protein even after induction of surface MHC-II expression by IFN-g or transduction with CIITA. These results suggest that priming and functional recognition of both a nuclear (E6) and a membrane-associated (KRAS) oncoprotein is predominantly confined to crosspresenting APC rather than via direct recognition of tumor cells induced to express MHC-II.
The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies such as immune checkpoint blockade (ICB), adoptive cellular therapy (ACT), and personalized cancer vaccines (PCV), highlighting their importance for antitumor immunity. While the functions of NeoAg-specific CD8+ T cells have been characterized, the role of NeoAg-specific CD4+ T cells is less well understood. To study the antitumor mechanisms of NeoAg-specific CD4+ T cells, we sorted single CD4+ T cells specific for a mutated clathrin heavy chain epitope (Cltc H129Q) expressed by the murine squamous cell carcinoma VII (SCC VII) tumor. T cell receptor (TCR) sequencing analysis revealed the presence of four distinct TCR clonotypes and expression of these TCRs in primary cells was sufficient to confer preferential recognition of Cltc H129Q as compared to the corresponding wildtype Cltc epitope. Despite differences in TCR avidity, both low and high avidity CD4+ T cells were capable of proliferating to similar degrees in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. ACT with Cltc H129Q specific CD4+ T cells also synergized with cyclophosphamide treatment to reduce disease burden in mice with established tumors. Overall, these findings illuminate the mechanistic role of NeoAg-specific CD4+ T cells in tumor immunity, provide insights into the impact of TCR avidity on the helper functions of CD4+ T cells, and highlight the therapeutic potential of ACT with TCR-engineered CD4+ T cells.
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