Taito Miyamoto

Live Birth Outcomes After Extended or Repeated High‐Dose Medroxyprogesterone Acetate Therapy for Fertility‐Sparing Management of Endometrial Neoplasia: A Single‐Center Retrospective Case Series

ABSTRACT Aim To clarify live birth outcomes among women receiving extended or repeated high‐dose medroxyprogesterone acetate (MPA) therapy for fertility‐sparing management of atypical endometrial hyperplasia or endometrioid carcinoma grade 1. Methods We conducted a single‐center retrospective case series of 53 patients undergoing MPA therapy between 2005 and 2023. Patients were stratified into three groups: (i) complete response (CR) within 6 months (standard group), (ii) CR after extended treatment beyond 6 months (extended group), and (iii) CR after MPA retreatment for first intrauterine recurrence (retreatment group). Primary outcome was the live birth rate (LBR). Secondary outcomes included the effect of initial reproductive intentions, interval from CR to conception, recurrence rates, and recurrence‐free interval (RFI). Results LBRs were 33% (10/30) in the standard group, 8% (1/12) in the extended group, and 17% (2/12) in the retreatment group. Among eight patients undergoing MPA retreatment for a second or subsequent recurrence, none achieved live birth. Patients with an initial desire for prompt conception had significantly higher LBRs than those without (38% vs. 5%, p < 0.01). Median time from CR to conception leading to live birth was 12 months. Patients achieving live birth had significantly longer RFIs than those without ( p < 0.01). Conclusions Live birth is most likely when CR is achieved within 6 months of MPA therapy; nonetheless, extended or repeated MPA treatment may still result in live birth. These findings suggest the importance of appropriate patient selection and careful monitoring during extended or repeated therapy and attempting conception promptly in fertility‐sparing management of endometrial neoplasia.

Myeloid activation clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of <30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk–dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression

Abstract New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2–CCR2–M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1–low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFNγ signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2–CCR2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3–high tumors had fewer tumoral IFNγ+CD8+ T cells and poorer prognosis than patients with B7-H3–low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2–CCR2–M2 macrophage axis–mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.

Selective Alanine Transporter Utilization Is a Therapeutic Vulnerability in ARID1A-Mutant Ovarian Cancer

Abstract Subunits of the SWI/SNF chromatin remodeling complex are altered in ∼20% of human cancers. Exemplifying the alterations is the ARID1A mutation that occurs in ∼50% of ovarian clear-cell carcinoma (OCCC), a disease with limited therapeutic options. In this study, we showed that ARID1A mutations create a dependence on alanine by regulating alanine transporters to increase intracellular alanine levels. ARID1A directly repressed the alanine importer SLC38A2 and simultaneously promoted the alanine exporter SLC7A8. ARID1A inactivation increased alanine utilization predominantly in protein synthesis and passively through the tricarboxylic acid cycle. Indeed, ARID1A-mutant OCCCs were hypersensitive to the inhibition of SLC38A2. In addition, SLC38A2 inhibition enhanced chimeric antigen receptor T-cell assault in vitro and synergized with immune checkpoint blockade using an anti–PD-L1 antibody in a genetically engineered mouse model of OCCC driven by conditional Arid1a inactivation in a CD8+ T-cell–dependent manner. These findings suggest that targeting alanine transport alone or in combination with immunotherapy may represent an effective therapeutic strategy for ARID1A-mutant cancers. Significance: ARID1A mutations regulate expression of alanine transporters to control alanine distribution between cancer cells and the associated tumor microenvironment, which may be exploited therapeutically alone or in combination with immunotherapy.