TIGIT transcriptomic expression and high levels of multiple checkpoints across diverse cancers.

Abstract

e14637 Background: The T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an immune inhibitory receptor present on some T- and natural killer (NK) cells. It plays an important role in restricting innate and adaptive immunity. Given this, studies to combine other checkpoint inhibitors with anti-TIGIT therapies are currently in development. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, (OmniSeq (https://www.omniseq.com/)). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high TIGIT expression (≥75 percentile rank) was calculated and Bonferroni corrected for multiple genes and cancer histologies with > 10 samples. Results: Of 514 tumors, 99 (19%) tumors had high TIGIT expression (32 different histologies). Cancers with the greatest proportion of high TIGIT expression were small intestine (33%; 4/12) pancreatic (31%; 17/55), lung (25%; 5/20), stomach (20%; 5/25), breast (20%; 10/49), colorectal (18%; 25/140), head and neck (17%; 2/12), sarcoma (13%; 3/24), and uterine (13%; 3/23), though there were no statistically significant associations between these histologies and high TIGIT. There were significant associations between high TIGIT and high PD-L1 (P < 0.0021), PD-1 (P < 0.0021), PD-L2 (P < 0.0021), CTLA-4 (P < 0.0021), OX40 (P < 0.0021), LAG3 (P < 0.0021), FOXP3 (P < 0.0021) expressions (p values Bonferroni adjusted for multiple comparisons). However, there was no significant association between tumor mutation burden ≥10 mutations/mb and high TIGIT. Conclusions: High TIGIT expression was found in 19% of 514 tumors (pan-cancer) and significantly associated with high RNA expression of other immune checkpoints (PD-L1, PD-1, PD-L2, CTLA-4, OX40, LAG3, FOXP3), many of which can be targeted by FDA-approved drugs or drugs in clinical trials. Ongoing studies combining TIGIT inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit after personalized tumor immune profiling.