Differences in Co-Expression of T Cell Co-Inhibitory and Co-Stimulatory Molecules with PD-1 Across Different Human Cancers.

Purpose: The promise of immune checkpoint inhibitor (ICI) therapy underlines the importance of comprehensively investigating the rationale for combinations with diverse immune modulators across different cancer types. Given the progress made with PD1 blockade to date, we examined mRNA co-expression levels of PD-1 with 13 immune checkpoints, including co-inhibitory receptors (LAG3, CTLA4, PD-L1, TIGIT, TIM3, VISTA, BTLA) and co-stimulatory molecules (CD28, OX40, GITR, CD137, CD27, HVEM), using RNA-Seq by Expectation-Maximization (RSEM).

Methods: We analyzed real-world clinical and transcriptomic data from the Total Cancer Care Protocol (NCT03977402) and Avatar project of patients with cancer treated within the Oncology Research Information Exchange Network (ORIEN) network. Using anti-PD1 as a backbone, we intended to investigate the rationale for combinations in different cancers. Pearson's R coefficients and associated P-values were calculated using SciPy 1.7.0.

Results: The co-expression of PD1 with 13 immune checkpoints and PD-L1 varies across selected malignancies included. In cutaneous melanoma, PD1 expression correlated significantly with four co-inhibitory receptors (LAG3, TIM3, TIGIT, VISTA) and one co-stimulatory molecule (CD137). In urothelial carcinoma, PD1 expression significantly correlated with four co-inhibitory (TIGIT, CTLA4, LAG3, VISTA) and four co-stimulatory (OX40, CD27, CD137, HVEM) molecules. In pancreatic adenocarcinoma, only CD28 showed a significant correlation with PD1 expression. No significant correlations with PD1 expression were found in the ovarian cancer cohort. Notably, melanoma and urothelial carcinoma exhibited a dominant co-expression of co-inhibitory molecules with PD1, indicative of exhausted T cells, in contrast to the co-stimulatory molecule dominance in ovarian and pancreatic cancers, suggesting less differentiated T cells.

Conclusions: Our findings highlight the potential for diverse combination strategies in immunotherapy, particularly with PD1 blockade, across various cancers.