Abstract 7526: Landscape of TIGIT and PD-L1 co-expression in solid tumors
Authors: Sarabjot Pabla, Maria-Fernanda Senosain, R.J. Seager, Hardik Parikh, Erik Van Roey, Shuang Gao, Yamuna Pulivendula, Paul DePietro, Mary Nesline, Durgapras Dash, Jeffrey M. Conroy, Stephanie Hastings, Heidi Ko, Kyle C. Strickland, Rebecca A. Previs, Eric Severson, Marcia Eisenberg, Brian Caveney, Taylor J. Jensen, Shakti Ramkissoon
Journal: Cancer Research (2024)

Abstract Background: Combination treatment of solid tumors with anti-PD-1/PD-L1 and anti-TIGIT agents have shown promise in recent clinical trials. However, TIGIT co-expression with other checkpoints has not been comprehensively characterized to support identification and prioritization of patients most likely to benefit from anti-TIGIT drugs and guide clinical trial design. In this study, we investigate TIGIT and other PD-1/PD-L1 axis checkpoint targets across various solid tumors. Methods: A discovery cohort (DC) of 24,186 solid tumors across 35 tumor types was evaluated by comprehensive immune profiling. TIGIT gene expression was normalized and ranked yielding a percentile rank values [0-100]. TIGIT rank was classified as high (rank &amp;gt;e 75) and low (rank &amp;lt; 25). We studied the distribution of TIGIT expression, cellular proliferation signature, and co-expression with PD-1/PD-L1 axis and other checkpoint targets using Spearman correlation(rs). Kaplan-Meier analysis and Chi-squared assessed associations between TIGIT expression/checkpoint co-expression and overall survival (OS), progression free survival (PFS) and objective response rate (ORR) differences in a separate cohort of 72 pembrolizumab treated non-small cell lung cancer (LC) patients treated with pembrolizumab. Results: The DC confirmed a large range of TIGIT expression with highest median expression observed in NSCLC (median = 61), head &amp; neck (HNSCC) (median = 59), and cervical cancer (median = 55). Significant association between PD-L1 IHC positivity (TPS≥1%, CPS≥1) and TIGIT expression (p&amp;lt;0.001) was discovered, where 69% (n=3574) of TIGIT high cases were PD-L1 positive, whereas 66% (n=3606) of TIGIT low cases were PD-L1 negative. By RNA-seq measurements, significant TIGIT co-expression (p&amp;lt;0.001) with various checkpoint blockade targets including PD-1 (rs=0.5), PD-L1 (rs=0.5), and TIM3 (rs=0.6) was confirmed. In the LC, patients with TIGIT high tumors had significantly improved OS (median OS = 44 months; p=0.01) and PFS (median PFS = 35 months; p=0.006) compared TIGIT low group (median OS = 23 months; median PFS = 18 months). Similar results were observed for response to pembrolizumab, where TIGIT high cases had significantly higher response (ORR=60%, p= 0.001) vs. TIGIT low cases (ORR=39%). This was confirmed in TIGIT high and PD-L1-IHC positive group with improved OS (p=0.013), PFS (p=0.017) and ORR (p=0.016). Conclusion: In an ultra-large cohort of clinically tested solid tumors, TIGIT was differentially expressed across tumor histologies of solid tumors. TIGIT expression was strongly co-expressed with PD-1/PD-L1 axis, supporting the improved outcomes for patients with NSCLC treated with a combination of TIGIT and PD-1/PD-L1 inhibitors from recent clinical trials. This finding of co-expression pattern of TIGIT and PD-1/PD-L1 axis highlights the potential use of immune profiling for combination therapy strategies and clinical trial design in solid tumors. Citation Format: Sarabjot Pabla, Maria-Fernanda Senosain, R.J. Seager, Hardik Parikh, Erik Van Roey, Shuang Gao, Yamuna Pulivendula, Paul DePietro, Mary Nesline, Durgapras Dash, Jeffrey M. Conroy, Stephanie Hastings, Heidi Ko, Kyle C. Strickland, Rebecca A. Previs, Eric Severson, Marcia Eisenberg, Brian Caveney, Taylor J. Jensen, Shakti Ramkissoon. Landscape of TIGIT and PD-L1 co-expression in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7526.