Bone is the most common metastatic site for breast cancer. Although the estrogen-related receptor alpha (ERRα) has been implicated in breast cancer cell dissemination to the bone from the primary tumor, its role after tumor cell anchorage in the bone microenvironment remains elusive. Here, we reveal that ERRα inhibits the progression of bone metastases of breast cancer cells by increasing the immune activity of the bone microenvironment. Overexpression of ERRα in breast cancer bone metastases induced expression of chemokines CCL17 and CCL20 and repressed production of TGFβ3. Subsequently, CD8+ T lymphocytes recruited to bone metastases escaped TGFβ signaling control and were endowed with exacerbated cytotoxic features, resulting in significant reduction in metastases. The clinical relevance of our findings in mice was confirmed in over 240 patients with breast cancer. Thus, this study reveals that ERRα regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth. Significance: This study places ERRα at the interplay between the immune response and bone metastases of breast cancer, highlighting a potential target for intervention in advanced disease.

Endometrial cancer (EC) is the seventh most common tumor in women, and prognosis of recurrent and metastatic disease is poor. Cervical cancer (CC) represents the fifth most common gynecological cancer. While ECs are more common in developed countries, the incidence of CC has decreased due to the recent implementation of large screening and vaccination programs. Until very recently, patients with advanced or unresectable EC or CC had very limited treatment options and were receiving in first line setting platinum/taxane-based chemotherapy (CT). Significant progress in the treatment of gynecological cancers has occurred in the last few years, with the use of innovative targeted therapies and immunotherapy. However, targeting the immune system in patients with gynecological tumors remains challenging and is not always successful. In ovarian cancer, several immunotherapy treatment regimens have been investigated (as monotherapy and combination therapy in first and subsequent lines of treatment) and showed poor responses. Therefore, we specifically focused our review on EC and CC for their specific immune-related features and therapeutic results demonstrated with immunotherapy. We report recent and current immunotherapy-based clinical trials and provide a review of emerging data that are likely to impact immunotherapy development based on increased biomarkers’ identification to monitor response and overcome resistance.

Purpose of review: Guidelines are essential to support appropriate medical management. The objective of our paper is to highlight the need for such recommendations, to reinforce strategies in place and to promote the creation of multidisciplinary networks to provide the most appropriate care to patients and to improve it. Recent findings: Gynecological rare cancers are not that rare since they represent around 50% of all gynecological cancers. Surgery remains the cornerstone of management for all subtypes. Apart from malignant ovarian germ-cell tumors for which conventional chemotherapy was proven to be efficient, response to standard systemic treatment for other gynecological cancers are disappointing. Better understanding of these pathologies is needed and requires more adapted management. Summary: Rare cancers are substantially heterogeneous but raise the need of integrating new cases in dedicated networks to enhance and homogenize medical practices. Centralized diagnosis, improved medical practice based on regularly updated international guidelines, and inclusion in innovative clinical trials linked to preclinical studies are essential to contribute to the promotion of improvement in patient care.

Combining immunotherapy with chemoradiation is effective in locally advanced cervical cancer. However, the impact of induction combination immunotherapy on immune modulation and treatment response is poorly understood. In this phase II trial (NCT04256213), 40 females with locally advanced cervical carcinoma received one cycle of nivolumab-plus-ipilimumab immunotherapy before standard chemoradiation, followed by maintenance nivolumab. We show, using multiplex-immunofluorescence tissue imaging, a significantly increased CD8⁺/FOXP3⁺ cell ratio (primary endpoint; increase of 0.87 cells/mm², P = 0.0164) and proliferative CD8⁺ T-cell density after one cycle of combination immunotherapy. HOT score (27-gene-based signature identifying immunologically active tumors) also increased significantly (exploratory analysis; 0.17, P < 0.0001). Objective response rates (secondary endpoint) were 13% immediately after combination immunotherapy, 98% (65% complete response) after chemoradiation, and 90% at treatment completion. High HOT score at baseline and immune changes induced by combination immunotherapy were associated with complete response at treatment completion. Induction immunotherapy may prime tumors for improved response to standard therapy.

Human and mouse primer sequences and PCR cycling and ChIP conditions used.