Analysis of Immune Checkpoints on Peripheral Blood Mononuclear Cells Can Predict Clinical Outcome and Reveal Potential of HVEM-BTLA Axis in Epithelial Ovarian Cancers

<b>Background/Objectives:</b> Immune checkpoint inhibitors (ICIs) do not provide promising benefits to patients with advanced epithelial ovarian cancer (EOC). This study analyzed preoperative peripheral blood mononuclear cells (PBMCs) from these patients to evaluate the prognostic and therapeutic checkpoints. <b>Methods:</b> Preoperative PBMCs of 69 advanced EOC cases were collected to analyze the correlation between IC-expressing immune cells and survivals of patients. Co-expression of various ICs on the T lymphocytes from these patients was examined. Activation potential of programmed cell death 1 (PD-1)⁺herpes virus entry mediator (HVEM)⁺ T cells in PBMCs from the healthy donors and tumoricidal abilities of PMBCs treated with various ICIs were evaluated in vitro. Impact of respective ICIs on activation of T cells in PMBCs was investigated. <b>Results:</b> Percentages of PD-1⁺ CD4⁺ and CD8⁺ T cells in the PBMCs of patients could positively correlate with disease-free or overall survival. HVEM was highly co-expressed on these T lymphocytes. Prediction potential for overall survival of patients by the subpopulation of PD-1⁺ CD4⁺ or CD8⁺ T cells was higher than that by other parameters. The PD-1⁺HVEM⁺ CD4+ and CD8⁺ T cells showed characteristics of activated phenotype under activation signals. PBMCs receiving anti-B and T lymphocyte attenuator (BTLA) plus anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) or anti-PD-1 Ab had potent tumor-killing ability. Anti-BTLA Ab can drive T cells in the PBMCs toward an effector status. <b>Conclusions:</b> Percentages of PD-1⁺ T cells in the PBMCs could predict survival of EOC patients. Targeting HVEM-BTLA axis may be considered for ICI treatment of EOCs.