The role of combined T cell and NK cell activity in immune checkpoint inhibitor (ICI) therapy in endometrial cancer (EC).

Abstract

5609 Background: The efficacy of ICI in EC has largely been attributed to high microsatellite instability (MSI-H) causing increased tumor mutational burden (TMB) and T-cell mediated immunity. However, a subset of patients with microsatellite-stable (MSS) tumors also derive clinical benefit, indicating that MSI status alone is insufficient for patient selection and contributing to the 2024 Food and Drug Administration approval of chemotherapy plus ICI for all patients with EC. We evaluated established biomarkers of a T-cell–inflamed tumor microenvironment alongside alternative immune pathways, notably natural killer (NK) cell activity, to define determinants of overall survival (OS) benefit in EC patients treated with ICI. Methods: Patients with EC treated with pembrolizumab or dostarlimab were identified from the Caris Life Sciences database with paired whole exome and transcriptome sequencing (WES/WTS). OS was defined from ICI initiation to death or last contact via insurance claims. Patients were grouped as long vs short survivors (LS/SS) by median post-ICI OS (mOS). Associations between OS and expression of pre-annotated T- and NK-cell-related genes were analyzed with Kaplan–Meier and multivariable Cox models adjusting for clinicopathologic factors. Results: Of 6,354 patients, 25% were MSI-H and 71% MSS. Immune deconvolution of WTS showed higher levels of CD8⁺ T cells (p=0.034) and regulatory T cells (p=0.026) in LS vs SS. In multivariable analyses of the MSS subset, 63 T- and NK-cell–related genes were associated with improved OS, including FASLG (mOS 19.7 months vs 14.7 months in LS vs SS, HR=0.77, CI 0.70–0.85), IFNG (mOS 18.9 months vs 15.5 months in LS vs SS, HR=0.78, CI 0.71-0.86) and SIRPG (mOS 18.8 months vs 15.6 in LS vs SS, HR=0.79, CI 0.71-0.87) (all p<0.0001). The IFN Tumor Inflammation Signature (TIS) was not associated with OS in MSS EC, whereas T-cell, NK-cell, and combined T/NK gene signatures were (Table 1). Conclusions: Improved OS after ICI in MSS EC is associated with both T-cell and NK-cell activity. NK-cell–related and combined T/NK signatures were associated with improved survival, suggesting NK-cell activation contributes to ICI efficacy. These findings warrant validation in independent cohorts prior to use as a potential biomarker for ICI use in MSS EC. T/NK signature scores are associated with improved OS in MSS EC. Label HR (95% CI) P value Gene set  NK (high vs low) 0.82 (0.74–0.90) <0.001  T + NK (high vs low) 0.84 (0.77–0.93) 0.001  T (high vs low) 0.84 (0.77–0.93) 0.001 Covariate  p53: mutant vs wildtype 1.54 (1.38–1.73) <0.001  TMB: high vs low 0.66 (0.49–0.90) 0.008  Chemotherapy: yes vs no 1.13 (0.98–1.31) 0.101  Biopsy site: metastasis vs primary 0.92 (0.83–1.02) 0.124  Lenvatinib: yes vs no 0.95 (0.86–1.05) 0.293 Multivariable Cox models adjusted for p53 status, TMB, site, chemotherapy and lenvatinib use.