title: Tumor-infiltrating Tim-3+T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk.
abstract: Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1low/intermedphenotype identifying recently activated and still functional cells, whereas PD-1hiTim-3-T cells are actually exhausted. Nonetheless, PD-1intermedcells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.
authors.affiliation: School of Medicine, Tsinghua University , Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Medicine, Tsinghua University , Beijing, China.
authors.forename: Gulidanna
authors.initials: G
authors.lastname: Shayan
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Graduate Program - Deptartment of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Avery
authors.affiliation: Department of Immunology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Hyun-Bae
authors.initials: HB
authors.lastname: Jie
authors.affiliation: Department of Immunology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Gildener-Leapman
authors.affiliation: Department of Immunology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Bin Feng
authors.initials: BF
authors.lastname: Lu
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
keywords: Activation; PD-1; TIL; Tim-3; exhaustion