PD-1 mediated regulation of CD8 +T cells in the murine submandibular gland

Abstract

Abstract Immune checkpoints, including programmed cell death protein 1 (PD-1), restrain the immune response, maintain self-tolerance, and prevent excessive collateral damage. Immune checkpoint blockade has revolutionized cancer immunotherapy by unleashing exhausted immune cells to kill tumor cells, but can lead to immune related adverse events (IrAEs). Patients receiving PD-1 blockade can develop IrAEs including vitiligo, colitis, endocrinopathies, and sicca syndrome, an autoimmune disease characterized by the accumulation of immune cells in the salivary and lacrimal glands, leading to deterioration and dysfunction. Because PD-1 is highly expressed on CD8 +T cells in the naive submandibular gland (SMG), we hypothesized that loss of PD-1 is likely to disrupt the previously reported hyporesponsive microenvironment of the SMG, leaving patients particularly susceptible to IrAEs affecting this gland. Our data indicates that genetic loss of PD-1 results in increased CD8 +T cell number and frequency in the SMG of naïve C57BL/6 animals. To characterize this expanding population, we recently collaborated with the ImmGen T consortium to perform single-cell RNA-seq on SMG T cells of wildtype and PD-1 knockout mice. Preliminary analysis indicates that the expanding CD8 +T cells in the salivary gland of PD-1 deficient animals have a unique phenotype. These cells exhibit exhaustion characteristics including expression of transcription factors Nr4a2and Tox, and inhibitory receptors LAG-3 and TIGIT. Altogether, our data provide insights for IrAE prevention and treatments in patients receiving PD-1 blockade. This work was supported by NIH research Grants AI46709 (L.B.), AI-072073 (ImmGen T), and a Brown University Presidential Award (S.B.). This work was supported by NIH research Grants AI46709 (L.B.), AI-072073 (ImmGen T), and a Brown University Presidential Award (S.B.).