Tumor-Stroma Context of T Cell Infiltration and Exhaustion in Ovarian Cancer Survival

Background: Tumor-infiltrating lymphocytes are associated with improved ovarian cancer (OC) survival in White women but not Black women despite similar T cell abundance. We evaluated whether exhaustion or localization of T cell infiltration may attenuate the survival advantage among Black women using a spatially informed compartment-specific approach to account for heterogeneity of whole tissue sections (WTS). Methods: Among 221 Black OC cases in the African American Cancer Epidemiology Study, multiplex immunofluorescence and HALO image analysis quantified total (CD3+) and cytotoxic (CD3+CD8+) T cells, along with exhausted (TIM3+) and terminally exhausted (TIM3+PD1+) subsets in FFPE WTS. PANCK-defined tumor and stroma were refined by excluding mixed interface regions detected using point-pattern intensities. Logit-transformed proportions were compared with paired t-tests. Cox proportional hazards estimated associations of compartment features with overall survival, adjusting for clinical factors. Results: Black OC cases were primarily advanced stage (58%) and high-grade serous carcinoma (HGSC; 69%); mean follow-up was 6.4 years. In tumor, 60% were T cell infiltrated (≥2% of tumor cells), and the median proportion of cytotoxic cells was 30%. Stroma contained 50% more T cells (p=9.1x10-12) but lower cytotoxic fractions (ΔT-S = -8%; p=3.9x10-19). Immune-excluded tumors (<2% tumor T cells) displayed strong stromal enrichment of total and cytotoxic T cells. Exhausted T cells were rare (1%) with tumors showing higher exhaustion (ΔT-S=1%, p=1.6x10-3) and terminal fractions (ΔT-S=15%, p=8.8x10-18) than stroma. Neither tumor nor stroma T cell abundance was associated with survival in univariate models. However, in compartment-adjusted models, tumoral cytotoxic T cells were associated with improved survival (hazard ratio [HR]=0.72, 95% confidence interval [CI]=0.53, 0.97), whereas stromal cytotoxic T cells were associated with worse survival (HR=1.65, CI=1.14, 2.37). A larger tumor-stroma gradient in cytotoxic T cells (> tumor) was similarly protective (HR=0.65, CI=0.48, 0.89). In HGSC, that had higher infiltration and exhaustion, infiltrated tumors had improved survival with higher exhaustion (HR=0.83, CI=0.70, 0.98) and terminal exhaustion (HR=0.88, CI=0.79, 0.99), while immune-excluded tumors did not. Conclusion: Distinct compartment-specific T cell and exhaustion patterns with divergent survival implications were observed in Black women with OC. Cytotoxic T cells confer a survival benefit only when tumor-dominant rather than stroma-dominant, highlighting the importance of characterizing an immune-exclusion phenotype. Improved survival with tumor T cell exhaustion likely indicates active antitumor immunity. WTS-based spatial profiling is essential for accurate interpretation of immune-survival relationships in Black women with OC. Citation Format: Brett M. Reid, Alex C. Soupir, Anthony J. Alberg, Elisa V. Bandera, Melissa L. Bondy, Michele L. Cote, Kristin Haller, Theresa Hastert, Carlos Moran Segura, Jonathan V. Nguyen, Edward S. Peters, Paul D. Terry, Andrew B. Lawson, Jeffrey R. Marks, Brooke L. Fridley, Joellen M. Schildkraut, Lauren Cole Peres. Tumor-stroma spatial context of T cell infiltration and exhaustion as determinants of ovarian cancer survival in Black women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6814.