IMMU-34. T cell receptor repertoire analysis of mouse glioma infiltrating CD4+ T cells reveals patterns of clonal T effector and T regulatory responses that may influence response to therapy

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Abstract Unlike in other cancers, anti-PD1 checkpoint blockade for patients with glioblastoma has failed in clinical trials to date. To improve immune system targeting therapies, particularly those that target T cells, we must understand antigen specificities and phenotypes of brain tumor infiltrating T cells. A major limitation of T cell clonal analysis in both human brain tumors and mouse models is high diversity within the T cell receptor (TCR) repertoire, making inter-individual comparison of T cell clones difficult. To address this challenge, we employ a fixed TCR beta chain transgenic mouse to decrease the total TCR repertoire to facilitate analysis of CD4+ T cell clonality in mouse models of high-grade glioma including CT-2A, GL261, and SB28. Additionally, we compare glioma infiltrating TCR repertoires to subcutaneously implanted tumor TCR repertoires including in MC38 colon adenocarcinoma, B16 melanoma, and 1956 sarcoma. Intracranial implantation of glioma cell lines results in large frequencies of Foxp3+ T regulatory (Treg) cells. TCR sequencing analysis of Foxp3-negative CD4+ T effector (Teff) cells and Treg cells reveals a mostly non-overlapping TCR repertoire between the two subsets, with individual T cell clones found in multiple mice. Comparison of TCR repertoires among tumor types demonstrates TCRs are variably specific for cell-of-origin, with a subset of overlapping TCR clones. Additionally, a subset of both Teff and Treg TCRs in brain tumors are also found in non-neoplastic tissues, indicating reactivity to self. Finally, a subset of glioma infiltrating T cell clones are dependent on type 1 conventional dendritic cells (cDC1s) for development. Overall, our findings suggest that glioma infiltrating T cell clones are reactive to distinct classes of antigens which engage in anti-tumor or pro-tumor activity. Future studies will examine whether antigen specific T cell classes differentially influence response to therapy in glioma.

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