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Neoantigen-specific stem cell memory-like CD4+ T cells mediate immunotherapy of solid tumors

ABSTRACT: The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies, highlighting the importance of these cells for antitumor immunity. While NeoAg-specific CD8+ T cells have been broadly studied, 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 an epitope derived from a mutated clathrin heavy chain gene (CLTCH129>Q) 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 CLTCH129>Q as compared to the corresponding wildtype CLTC epitope. Despite differences in TCR avidity, both moderate and high avidity CD4+ T cells were capable of proliferating to similar levels in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. Finally, we demonstrate that adoptive cellular therapy (ACT) with T stem cell memory (TSCM)-like CLTCH129>Q-specific CD4+ T cells differentiated ex vivo in culture with IL-7 and IL-15 promotes therapeutic tumor immunity associated with enhanced T cell persistence, maintenance of adoptively transferred TSCM-like cells in the tumor-draining lymph node (tdLN), and activation of CD8+ T cells in the tdLN. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE229221 | GEO | 2023/05/24

REPOSITORIES: GEO

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Project description:The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. Together, these findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.

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Neoantigen-specific stem cell memory-like CD4+ T cells mediate immunotherapy of solid tumors

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