Abstract Background: Ovarian cancer remains the deadliest gynecologic malignancy, with limited benefit from immune checkpoint therapy (ICT), particularly in high-grade serous carcinoma (HGSC). A substantial proportion of patients present with thrombocytosis, a feature linked to poor survival. Platelets can promote tumor immune evasion by shielding cancer cells and suppressing CD8+ T cell function, yet the mechanisms underlying platelet-driven immune resistance in ovarian cancer remain poorly defined. Clarifying these pathways may reveal new strategies to improve ICT response. Methods: Immune infiltration was analyzed in 362 ovarian cancer patients stratified by platelet levels using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORTx) algorithm. Opal multiplex immunofluorescence on human ovarian tumors quantified intratumoral platelets, programmed death-ligand 1 (PD-L1), podoplanin (PDPN), and neutrophils. Functional effects of platelet–immune interactions were assessed using co-cultures of ovarian cancer cells with CD8+ T cells ± platelets, followed by measurement of CD8+ T cell–mediated cytotoxicity and flow cytometric evaluation of T cell exhaustion markers. Results: High platelet counts in ovarian tumor microenvironment (TME) were associated with reduced CD8+ T cell infiltration compared with low-platelet tumors. Patients with elevated platelet levels displayed altered immune signatures, a pattern recapitulated in The Cancer Genome Atlas (TCGA) tumors stratified by glycoprotein 1b alpha (GP1bα) expression. High-platelet TMEs also exhibited increased PD-L1 and PDPN expression and enhanced neutrophil infiltration. Functionally, platelets impaired CD8+ T cell cytotoxicity toward ovarian cancer cells in vitro and promoted a more exhausted CD8+ T cell phenotype. These data suggest that CD8+ T cells infiltrating high-platelet tumors are present but functionally compromised. Conclusion: These findings indicate that platelets promote an immunosuppressive TME in ovarian cancer by impairing CD8+ T cell infiltration and function. Targeting platelet–tumor interactions may help reverse T cell dysfunction and enhance immunotherapy efficacy. Citation Format: Robiya Joseph, Sara Corvigno, Min Soon Cho, Vahid Afshar-Kharghan, Zhiqiang An, Anil K. Sood, Ningyan Zhang. Overcoming platelet-mediated immune suppression in ovarian cancer abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A045.
Joseph et al. (Wed,) studied this question.