TIM-3 transcriptomic landscape with clinical and immunomic correlates in cancer.

ABSTRACT

TIM-3, an inhibitory checkpoint receptor, may invoke anti-PD-1/anti-PD-L1 immune checkpoint inhibitor (ICI) resistance. The predictive impact of TIM-3 RNA expression in various advanced solid tumors among patients treated with ICIs is yet to be determined, and their prognostic significance also remains unexplored. We investigated TIM-3 transcriptomic expression and clinical outcomes. We examined TIM-3 RNA expression data through the OmniSeq database. TIM-3 transcriptomic patterns were calibrated against a reference population (735 tumors), adjusted to internal housekeeping genes, and calculated as percentiles. Overall, 514 patients (31 cancer types; 489 patients with advanced/metastatic disease and clinical annotation) were assessed. Ninety tumors (17.5% of 514) had high (≥75th percentile RNA rank) TIM-3 expression. Pancreatic cancer had the greatest proportion of TIM-3 high expressors (36% of 55 patients). Still, there was variability within cancer types with, for instance, 12.7% of pancreatic cancers harboring low TIM-3 (<25th percentile) levels. High TIM-3 expression independently and significantly correlated with high PD-L2 RNA expression (odds ratio (OR) 9.63, 95% confidence interval (CI) 4.91-19.4, P<0.001) and high VISTA RNA expression (OR 2.71, 95% CI 1.43-5.13, P=0.002), all in multivariate analysis. High TIM-3 RNA did not correlate with overall survival (OS) from time of metastatic disease in the 272 patients who never received ICIs, suggesting that it is not a prognostic factor. However, high TIM-3 expression predicted longer median OS (but not progression-free survival) in 217 ICI-treated patients (P=0.0033; median OS, 2.84 versus 1.21 years (high versus not-high TIM-3)), albeit not retained in multivariable analysis. In summary, TIM-3 RNA expression was variable between and within malignancies, and high levels associated with high PD-L2 and VISTA checkpoints and with pancreatic cancer. Individual tumor immunomic assessment and co-targeting co-expressed checkpoints merits exploration in prospective trials as part of a precision immunotherapy strategy.