| First Author | Li J | Year | 2016 |
| Journal | Oncoimmunology | Volume | 5 |
| Issue | 10 | Pages | e1200778 |
| PubMed ID | 27853635 | Mgi Jnum | J:279177 |
| Mgi Id | MGI:6356439 | Doi | 10.1080/2162402X.2016.1200778 |
| Citation | Li J, et al. (2016) Tumor-infiltrating Tim-3(+) T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk. Oncoimmunology 5(10):e1200778 |
| abstractText | 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-1(low/intermed) phenotype identifying recently activated and still functional cells, whereas PD-1(hi)Tim-3(-) T cells are actually exhausted. Nonetheless, PD-1(intermed) cells 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. |
