TIGIT expression and outcomes in pembrolizumab treated patients with NSCLC.
Authors: Senosain Maria-Fernanda , Seager Robert J. , Van Roey Erik , Gao Shuang , DePietro Paul , Nesline Mary K , Dash Durga P. , Conroy Jeffrey M. , Hastings Stephanie , Ko Heidi Chwan , Strickland Kyle C , Previs Rebecca A. , Severson Eric A , Jensen Taylor J. , Reddy Venkataprasanth P. , Ramkissoon Shakti , Pabla Sarabjot 
Published: June 2023

e21110 Background: Immune checkpoint inhibitors (ICIs) have emerged as effective treatments for multiple cancers. TIGIT is an emerging ICI target that impairs T cell activation by dendritic cells, enhances the immune suppressive activity of regulatory T cells, and inhibits tumor killing by natural killer and cytotoxic T cells. In this study, we describe the mRNA expression landscape of TIGIT across 35 solid tumor types, its co-expression with additional checkpoint targets, and correlation with survival of patients with Non-Small Cell Lung Cancer (NSCLC) treated with pembrolizumab. Methods: A discovery cohort (DC) of 15,630 tumors across 35 types were evaluated by comprehensive immune profiling. TIGIT expression was ranked across a population of 735 samples to yield rank values [0-100]. TIGIT rank was grouped as high (rank ≥75) and low (rank < 25). We assessed the distribution of TIGIT expression across cancer types, cellular proliferation, and significant co-expression with other checkpoint targets. Co-expression was assessed using Spearman correlation(rs). Additionally, in a retrospective cohort (RC) of 72 pembrolizumab treated patients with NSCLC, Kaplan-Meier analysis was used to test for differences in overall survival (OS) and progression free survival (PFS). Differences in objective response rate (ORR) were determined using chi squared test. Results: The DC demonstrated a dynamic range of TIGIT expression with highest median expression observed in lung cancer (median rank = 60) where 36% of lung cancers were TIGIT high. Tumors with high expression of proliferation markers including Ki67 were predominantly TIGIT high (87.5%; p < 0.001), whereas tumors with poor proliferation were TIGIT low (73.5%, p < 0.001). TIGIT was found to be significantly co-expressed (p < 0.001) with other immunotherapy targets including PD-1 (rs= 0.5), PD-L1 (rs= 0.5), and TIM3 (rs= 0.6) by RNA-Seq. For dual expression, we identified subgroups that are both PD-1 high and TIGIT high (2766/15,630; 17%). Similar results were observed for TIGIT and PD-L1 dual expression (PD-L1 high and TIGIT high 2167/15,630; 14%). TIGIT high patients from the NSCLC RC demonstrated significantly higher OS (median OS = 44 months; p = 0.01) and PFS (median PFS = 35 months; p = 0.006) compared the TIGIT low patients (median OS = 23 months; median PFS = 18 months). TIGIT high cases had significantly (ORR = 60%, p = 0.001) improved response to pembrolizumab compared to TIGIT low cases (ORR = 39%). Conclusions: Comprehensive immune profiling of a clinically tested pan-cancer cohort showed that TIGIT is a potential immune target with dynamic expression across multiple solid tumors. TIGIT expression is strongly associated with proliferation and suggests improved outcomes for NSCLC cancer patients treated with an ICI therapy. Furthermore, significant TIGIT co-expression with other checkpoint targets such as PD-1/PD-L1 highlights its potential use in combination therapy strategies.