PD1-independent CD8 T cell exhaustion driven by the loss of UFL-1 2260778
TL;DR
It is found that UFL1-deficient CD8 T cells undergo exhaustion during acute viral infection, and the findings suggest that exhaustion in UFL1-deficient CD8 T cells is PD1-independent.
Abstract
Cytotoxic CD8 T cells play a crucial role in eliminating infections and cancer. However, chronic antigen exposure induces their development into exhausted T (TEX) cells. TEX cells exhibit increased inhibitory receptors or checkpoints expression, defective effector functions and thus unable to eliminate the virus-infected cells and cancers. Antibodies inhibiting signaling through checkpoints PD1 or CTLA4 (immune checkpoint blockade or ICB) induce differentiation of TEX cells into effectors that eliminate cancer and viral infected cells. PD1 blockade is the leading ICB against several tumor types. However, > 50% of the cancer patients either do not respond or get durable benefits from PD1 blockade. Therefore, there is an urgent need to understand the PD1-independent mechanism to improve immunotherapy against tumors resistant to PD1 blockade. In order to address the role of UFL-1 in CD8 T cell exhaustion, we used LCMV acute and chronic infection models in control and CD4 specific UFL-1 knockout mice. Different subset of CD8 T cells and their differentiation status and functional response upon activation were analyzed using flow cytometry and ScRNA-seq. Acute exposure to antigens, is not known to cause T cell exhaustion. We found that UFL1-deficient CD8 T cells undergo exhaustion during acute viral infection. During chronic antigen presence, such as in tumor models and chronic viral infections, UFL1 deficiency worsens CD8 T cell exhaustion. Additionally, the PD1 blockade fails to improve the functionality of UFL1-deficient TEX cells. Consistent with this, UFL1 expression in tumor-infiltrating CD8 T cells is positively correlated with the progression-free survival of melanoma patients treated with PD1 blockade. These findings suggest that exhaustion in UFL1-deficient CD8 T cells is PD1-independent. Therefore, understanding how UFL1 prevents T cell exhaustion would help discover new ways to improve immunotherapies, especially for cancers that do not respond to PD1 blockade. NIH Funding - NIAID00054 Immune Response Regulation: Molecular Mechanisms (IRM)