743 Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

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Background CD8 + tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to differentiation to T cell exhaustion. In healthy tissues, tissue-resident memory T cells (TRM) survey tissues and sustain protective capacity for years, and tumors that contain TIL with TRM-features are associated with better patient prognosis.Methods We utilized tumor-specific CD8 + T cells retrovirally-transduced for gene overexpression or CRISPR for loss-of-function studies, and adoptively transferred T cells into LCMV virally-infected mice or MC38 and B16 tumor-bearing mice. We also employed low-input mass spectrometry for unbiased proteomics, allowing for the identification of >8,000 unique proteins from ex vivo-sorted T cells.Results We identified protein homeostasis (proteostasis) as a significant factor distinguishing T RM and progenitor-exhausted TIL (TPEX) from terminally-exhausted TIL (TEX) by identifying multiple E3 ubiquitin ligases that maintain T cell differentiation potential. Sustained ligase-expression in TIL enhanced T cell accumulation, preserved stem-like TCF1+ populations, and improved anti-tumor function, whereas ligase loss-of-function impaired TIL and altered T cell differentiation in acute infection. TEX experienced a loss of proteostasis, marked by accumulation of unfolded proteins despite functional proteasomes, and enforced ligase expression rescued this accumulation of unfolded proteins in TIL and improved immunotherapy responses.Conclusions Proteostasis is essential for maintaining T cell differentiation potential, and engineering TIL proteostasis is a new modality for advancing cancer immunotherapy.Ethics Approval The study was approved by UCSD’s Institutional Animal Care and Use Committee, protocol number S04105.

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