Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL. However, it is not known whether there is molecular cross-talk between PD-1 and Tim-3, which is a relevant question as we have observed a prominent double-positive population of CD8+ T cells in HNSCC patients' tumor infiltrating lymphocytes (TIL). In most settings, the acquisition of multiple checkpoint inhibitors is associated with more severe functional impairment than expression of only one such inhibitory protein. Given the frequent co-expression of PD-1 and Tim-3 on HNSCC patient TIL, the potential for cross-talk between this signaling pathway, also known to regulate Tim-3 expression and function, motivates this proposal. We hypothesize that PD-1 and Tim-3 work cooperatively to control the function of exhausted/effector TIL, and that modulation of PD-1 and Tim-3 crosstalk through PI3K/Akt/mTOR will enhance T cell activation.
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