CNPY2-orchestrated unfolded protein responses play redundant roles in regulating anti-tumor immunity of CD8 +T cells

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Abstract Tumors evade immune surveillance by creating a hostile environment that impairs the functions of immune cells. Persistent perturbations including chronic antigen stimulation and metabolic challenges cause endoplasmic reticulum (ER) stress and unfolded protein responses (UPR) in T cells. CNPY2 is one of the key initiators of UPR in the ER, but its roles in T cell activation and persistence have not been reported. Herein, we found that the expressions of CNPY2 and other molecules in UPR pathways were upregulated in both activated and exhausted T cells, indicating UPR activation. However, genetic deletion of Cnpy2 in CD8 +T cells did not result in changes in viability, proliferation, mitochondrial functions, and protein translation rate under acute or chronic antigen stimulation in vitro. Furthermore, no differences were seen between wild-type and CD8-specific Cnpy2 knockout mice in protection against multiple syngeneic tumor models including colon (MC38 and CT26), bladder (MB49), melanoma (YUMM1.7 and B16-F10) and breast tumors (4T1). Although CD8 +T cells from tumors were moderately more activated in the absence of CNPY2, no apparent impact was observed on CD8 +infiltration and effector differentiation. Finally, by mRNA profiling and proteomic analysis, we found that the downstream UPR signaling pathways remained intact in T cells despite loss of CNPY2. In summary, we concluded that persistent TCR stimulation and the tumor microenvironment induce CNPY2 expression and UPR in CD8 +T cells. However, ablating CNPY2 alone failed to overcome UPR-mediated T cell dysfunction, suggesting that targeting multiple initiators of UPRs in CD8 +T cells need to be considered to improve cancer immunotherapy.