A recent study published in Cell has identified effector regulatory T cells (eTregs) as a promising immunotherapeutic target for ovarian cancer, particularly in tumors with homologous recombination deficiency (HRD). The research, led by Luo and colleagues, combined clinical trial data with multi-omics analysis to understand how PARP inhibitors reshape the tumor microenvironment in ovarian cancer.
Unmet Needs in Ovarian Cancer Treatment
Ovarian cancer remains a significant challenge, marked by high mortality and low 5-year survival rates. Epithelial ovarian cancer, comprising 90% of cases, includes high-grade serous ovarian cancer (HGSOC), characterized by genomic instability and frequent TP53 mutations. While PARP inhibitors have shown benefit in HRD-positive patients, PD-(L)1 immunotherapy has not yielded similar survival advantages. This highlights the need for innovative therapeutic approaches, especially for patients ineligible for surgery or resistant to platinum-based chemotherapy.
Clinical Trial and Multi-Omics Analysis
To investigate the impact of PARP inhibitors and HRD status on the tumor microenvironment, the researchers conducted a clinical trial (NANT, NCT04507841) using neoadjuvant niraparib monotherapy in advanced HRD ovarian cancer. Patients receiving neoadjuvant chemotherapy (NACT) served as controls. The study included patients with both homologous recombination-proficient (HRP) and HRD status. Multi-omic profiling, including single-cell T cell receptor sequencing (scTCR-seq), bulk TCR sequencing, and multiplex immunohistochemistry (mIHC), was performed on tumor and blood samples.
Key Findings: eTregs as a Therapeutic Target
Clinical monitoring showed a 73.6% response rate (RR) in HRD patients treated with niraparib, with a good safety profile. Single-cell transcriptome sequencing revealed that chemotherapy and niraparib affected similar cell populations. Notably, eTregs were uniquely enriched in HRD-HGSOC and following NANT treatment, co-occurring with terminally exhausted CD8+ T cells (Texs). The enrichment of eTregs in the HRD state diminished after niraparib and platinum chemotherapy. Further analysis indicated that tumor cells may recruit or activate eTregs through high expression of type II MHC molecules and co-inhibitory molecules.
Preclinical Validation with CCR8 Targeting
Given that C-C chemokine receptor type 8 (CCR8) is a marker for eTregs, the researchers tested the therapeutic potential of targeting CCR8. They constructed CCR8-humanized mice and used a humanized therapeutic monoclonal antibody (mAb) targeting CCR8 (ZL-1218, currently in phase I clinical trials, NCT05859464). In an orthotopic mouse model of HGSOC, combining niraparib with the CCR8 mAb resulted in a more pronounced inhibitory effect on tumor progression compared to either treatment alone. Similar results were observed with a CD25 mAb, another Treg-depleting therapy. These findings suggest that targeting eTregs in combination with niraparib could be particularly effective in HRD ovarian cancers.
Implications for Personalized Medicine
This study exemplifies reverse translational medicine (RTM), bridging clinical observations with fundamental biological insights. By dynamically characterizing the treatment-perturbed microenvironment and patient outcomes, the researchers identified key responsive cell populations and molecular targets. The preclinical validation of combination therapies targeting eTregs and niraparib highlights the potential for personalized treatment approaches in ovarian cancer and other advanced solid tumors.
