Immunotherapy and Ovarian Cancer: Toward Enhanced Treatment Response?

Ovarian cancer is a serious condition, often diagnosed at an advanced stage, which makes its treatment challenging. Immunotherapy, which aims to stimulate the immune system to combat cancer, holds promise for improving treatment outcomes. Specifically, combining immunotherapy with current treatments — such as PD-1 inhibitors like pembrolizumab — has garnered growing interest in clinical research. However, despite the high immunogenicity of ovarian cancer, particularly high-grade serous carcinoma (HGSC), responses to PD-1 blockade remain limited, with only modest improvements in survival rates.

This study was therefore launched not only to explore mechanisms of immunoresistance in ovarian cancer but also to propose pathways to enhance the effectiveness of immunotherapy.

What Are the Effects of the Combined NACT + Pembrolizumab Treatment?

Researchers analyzed tumor samples from a phase II clinical study aimed at evaluating the effectiveness of combining neoadjuvant chemotherapy (NACT) with pembrolizumab in treating high-grade ovarian cancer. They utilized a multi-omic approach, combining transcriptomic analysis with multi-color immunofluorescence, to understand the treatment’s impact on the tumor microenvironment and identify predictive biomarkers of response to immunotherapy.

The study initially demonstrated that the NACT/pembrolizumab combination is associated with a significant increase in intraepithelial CD8+PD-1+ T cells within the tumor microenvironment — a marker of immune activation.

Additionally, certain molecular signatures were linked to increased resistance to the combined treatment. For instance, high VEGFR2 expression on tumor endothelial cells was associated with reduced immune infiltration and lower survival rates in patients receiving the combined treatment. Similarly, elevated levels of M2 macrophages, which contribute to a suppressive microenvironment, were correlated with immune resistance and shorter survival. Finally, the CD8B/FOXP3 expression ratio and the association of endothelial and monocytic gene signatures proved to be predictive of response to the combined treatment, with high accuracy (AUC = 0.93).

New Avenues to Improve Immunotherapy Effectiveness in Ovarian Cancer

This study highlights the crucial role of the tumor microenvironment in immunotherapy response in ovarian cancer. Specifically targeting regulatory T cells and VEGFR2+ endothelial cells may help overcome certain mechanisms of immunoresistance and improve treatment efficacy. Combined therapeutic approaches and the development of VEGFR2 inhibitors thus represent promising avenues to maximize the clinical benefits of immunotherapy in ovarian cancer.