Chemotherapy driven alterations in NK cell receptors and ligands in high grade serous ovarian cancer

Introduction: Combination approaches are being explored to improve immunotherapy efficacy, yet the immunomodulatory effects of chemotherapy on NK cell receptors and their ligands remain unexplored in high-grade serous ovarian cancer (HGSOC). Therefore, understanding chemotherapy-induced immune modulation is essential in HGSOC. Methods: Immune profiling was conducted on clinical specimens from 33 chemo-naïve patients undergoing primary debulking surgery (PDS), 57 chemotherapy-treated patients undergoing interval debulking surgery (IDS), and 17 patients in the IDS group were followed during chemotherapy cycles. Immune profiling was carried out using flow cytometry, Procartaplex immunoassay, and ELISA. Blood samples were collected from 50 age- and gender-matched healthy participants for comparison. Results: Primary investigation on follow-up patients reveals chemotherapy-mediated immune modulation on NK cell subsets. This was further validated in the chemo-treated surgical cohort. The Natural Cytotoxicity Receptors (NCRs) were downregulated on NK cells in chemo-naïve surgical cohorts. The NCR group of receptors was normalized to a level comparable to that in healthy controls in the chemotherapy-treated surgical cohort, due to reduced soluble ligands. Surface MICA expression was also increased (p = 0.0466) on EpCAM+ cells in the chemo-treated surgical cohort compared to the chemo-naïve surgical cohort, while NKG2D+ immune cells were reduced in both surgical cohorts compared to healthy controls. Moreover, proinflammatory cytokines IL-2 (p = 0.0001) and TNF-α (p = 0.0442) were reduced in the chemotherapy-treated surgical cohort, while intracellular levels of dual perforin and granzyme were elevated in the chemo-treated group, which may enhance cytolytic potential. High surface expressions of HLA-E, MIC-B, and LLT-1 ligands were associated with improved progression-free survival. Conclusions: Our findings highlight the broad immunomodulatory effects of chemotherapy on NK cell receptors, ligands, and cytokines, which may offer insights for combination therapies in HGSOC.