Immune Environment and Immunotherapy in Endometrial Carcinoma and Cervical Tumors.

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.

Treatment Perspectives for Ovarian Cancer in Europe and the United States: Initial Therapy and Platinum-Sensitive Recurrence after PARP Inhibitors or Bevacizumab Therapy.

PURPOSE OF REVIEW: Although the survival rate of patients with ovarian cancer (OC) has significantly improved, OC is still one of the most common causes of gynecologic cancer death in women worldwide. The current advances in primary treatment are based on recent regulatory approvals and recurrency of such treatments, challenging the development of a unified approach to care. Herein, we examine how integration of these new approaches is applied to patient's treatment. RECENT FINDINGS: We and others have recently reported clinical trials using bevacizumab and/or inhibitors of Poly (ADP-ribose) polymerase (PARP), which have greatly affected the change in first-line treatments for OC. As first-line therapy has evolved, therapeutic agents once designated for recurrent disease are increasingly being incorporated, changing our standard of care following previously indexed trials. Here, we provide an overview of the current treatment for OC patients, and we highlight practice patterns in Europe and in the USA with corresponding opinions on current and future treatments for platinum-sensitive recurrent OC.

Regulatory T cells promote cancer immune-escape through integrin αvß8-mediated TGF-ß activation.

Presence of TGFß in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFß is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the ß8 chain of αvß8 integrin (Itgß8) are the main cell type in the tumors that activates TGFß, produced by the cancer cells and stored in the tumor micro-environment. Itgß8 ablation in Treg cells impairs TGFß signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8+ T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgß8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFß and to create an immunosuppressive micro-environment.

Importance of guidelines and networking for the management of rare gynecological cancers.

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.

Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells.

Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-ß8 endows the bioavailability of transforming growth factor-ß in the microenvironment, thereby promoting the generation of CD8+ TRM cells.

ERRα Expression in Bone Metastases Leads to an Exacerbated Antitumor Immune Response.

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 TGFß3. Subsequently, CD8+ T lymphocytes recruited to bone metastases escaped TGFß 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.

Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.