高级别浆液性卵巢癌患者接受PARPi+ATRi联合治疗后免疫活性增强

Introduction: Complete responses to PARP inhibitor (PARPi) monotherapy in recurrent high-grade serous ovarian cancer (HGSOC) are rare. However, preclinical data have demonstrated promising synergy between PARP and ATR inhibitors. Characterizing the immune contexture of the tumor microenvironment and the surrounding stroma during treatment may provide valuable biological insights into the efficacy of this combination therapy and inform future combinations. Methods: Patients with recurrent HGSOC received ceralasertib 160mg orally daily, days 1-7 and olaparib 300mg twice daily, days 1-28 of a 28-day cycle. 18 tissue samples were collected across archival (resection) and pre-treatment and on-treatment timepoints (core biopsies). Each sample was analyzed using a 25-plex multiplex immunohistochemistry (mIHC) assay, which interrogates cell composition and functional states of neoplastic and immune cell types, including all major lymphoid and myeloid populations. Segmented cells were assigned to either a tumor or stroma compartment using a PanCK mask that was uniformly expanded by 25μm, and average cell densities were calculated for each compartment. Results: Samples obtained during combination PARPi + ATRi treatment demonstrated widespread increases in immune cell densities including T cells (CD8+, Tregs, and Th1-like cells), B cells, dendritic cells, macrophages, and monocytes. Among the T-cell populations, higher densities of Granzyme B and PD-1 were observed, indicating enhanced cytotoxic activity and immune engagement. Concurrently, there was a decrease in proliferating neoplastic cells (PanCK⁺Ki67⁺), consistent with reduced tumor cell proliferation during treatment. Using the PanCK tumor mask, we observed that CD8⁺ T cells, Th1-like cells, B cells, and dendritic cells increased more prominently within the tumor compartment compared to the surrounding stroma. Samples obtained prior to treatment from patients with stable or progressive disease (SD/PD) exhibited higher macrophage densities, primarily attributable to elevated levels of M2-like (immunosuppressive) macrophages. Conclusions: The increased immune cell densities measured by mIHC indicate overall activation of the immune system following PARPi + ATRi treatment. Elevated levels of PD-1⁺ and Granzyme B⁺ T cells suggest enhanced immune activation and cytotoxic potential, while comparative analysis of the tumor versus stroma compartments demonstrates improved immune cell infiltration into the tumor. Notably, higher baseline densities of M2-like macrophages may influence or limit response to therapy. Collectively, these findings provide evidence that PARPi + ATRi combination therapy promotes anti-tumor immune activity. However, additional data is needed to correlate these immune changes with clinical outcomes.