Insights into Ovarian Tumor Immune Microenvironment Offer New Therapeutic Avenues

Ovarian cancer remains one of the deadliest gynecologic malignancies, with patient responses to standard treatments heavily influenced by the tumor's immune landscape. Recent research has significantly advanced our understanding of how the immune system interacts with ovarian tumors, especially during recurrence. A comprehensive study conducted by Ludwig Lausanne researchers, led by Denarda Dangaj Laniti and Eleonora Ghisoni, analyzed the immune profiles of both primary and recurrent ovarian tumors, revealing critical insights that could enhance therapeutic strategies.

The study, published in the journal Cancer Cell, is the largest of its kind, examining hundreds of tumor samples. It identified four distinct immunologic subtypes of recurrent ovarian cancers, each characterized by differing levels of immune cell infiltration and related to specific genomic features. This classification hinges on the presence of CD8⁺ T lymphocytes — the primary cells responsible for attacking cancer — revealing whether tumors are "purely inflamed," "mixed inflamed," "excluded," or "desert."

Patients with "inflamed" tumors, which have high infiltration of immune effector cells, tend to have better survival rates, especially if their tumors contain mutations impairing DNA repair mechanisms like BRCA1. Conversely, tumors with limited immune infiltration, classified as "excluded" or "desert," are associated with poorer outcomes and exhibit mechanisms that enable immune evasion.

The study highlights the importance of myeloid cells, such as macrophages and dendritic cells, in shaping the tumor microenvironment upon recurrence. Notably, tumors with proficient DNA repair mechanisms often recruit immunosuppressive macrophages marked by ApoE and Trem2 proteins, which can hinder immune responses.

Targeting these myeloid cells shows promise; for example, inhibiting Trem2 in mouse models improved chemotherapy response and delayed tumor progression. Conversely, inflamed tumors rich in T cells and dendritic cells retain their immune-supportive niches during recurrence, offering prime targets for immunotherapy.

The research uncovers a key immune-evasion pathway driven by COX enzyme activation in inflamed tumors, which leads to the secretion of PGE2, a molecule that suppresses tumor-infiltrating lymphocytes (TILs). Combining COX inhibitors with PARP inhibitors like olaparib and chemotherapy in preclinical models doubled survival time, further enhanced by checkpoint blockade immunotherapy.

These findings suggest that patients with DNA repair-deficient inflamed tumors could be ideal candidates for immunotherapy trials. Meanwhile, strategies like TREM2 inhibition might be effective against more suppressive tumor subtypes. Overall, this research underscores the importance of personalized approaches targeting both the tumor cells and the immune cells that facilitate immune resistance, paving the way for more effective ovarian cancer treatments.