Nan Zhang

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.

Low L3 skeletal muscle index associated with the clinicopathological characteristics and prognosis of ovarian cancer: a meta‐analysis

AbstractSarcopenia is a syndrome characterized by progressive loss of skeletal muscle mass, strength and function, which is one of the most important clinical features of cancer malnutrition, representing a poor prognostic indicator in oncology. Sarcopenia is commonly assessed by measuring the skeletal muscle index (SMI) of the third lumbar spine (L3) using computed tomography (CT). The primary aim of this meta‐analysis was to study the association between low SMI and comprehensive clinicopathological characteristics as well as prognosis in patients with ovarian cancer. Data were searched in PubMed, EMBASE and Cochrane databases from inception to 10 June 2022. Studies evaluating the prognostic effect of SMI on ovarian cancer survival or chemotherapy‐related side effects were included. The risk of bias and study quality were assessed via the Newcastle–Ottawa Scale (NOS). The search strategy yielded 1286 hits in all three databases combined. Thirteen studies were included for qualitative and quantitative analysis, comprising 1814 patients. Our meta‐analysis revealed the significant association between low SMI and progression‐free survival (PFS) [P = 0.02; hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.06–1.85], as well as 5‐year overall survival (OS) [P = 0.02; odds ratio (OR): 1.35, 95% CI: 1.05–1.74]. Low SMI was also obviously associated with body mass index (BMI) < 25 (P < 0.00001; OR: 5.08, 95% CI: 3.54–7.30), FIGO stage (P = 0.02; OR: 1.62, 95% CI: 1.06–2.45) and R0 cytoreduction (P = 0.04;OR: 1.34, 95% CI: 1.01–1.79). There was no correlation between low SMI and histological types, pathological grades and chemotherapy‐related toxicity. The quality of the evidence was relatively high according to NOS. Our meta‐analysis indicated that sarcopenia assessed by SMI was associated with poor clinical characteristics and adverse prognosis in patients with ovarian cancer. Consensus should be reached on standardized cut‐off values for defining sarcopenia in patients with ovarian cancer.

LYVE1+ macrophages of murine peritoneal mesothelium promote omentum-independent ovarian tumor growth

Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/− and LYVE1lo/− MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fate-mapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the omentum. Indeed, syngeneic epithelial ovarian tumor growth was strongly reduced following in vivo ablation of LYVE1hi macrophages, including in mice that received omentectomy to dissociate the role from omental macrophages. These data reveal that the peritoneal compartment contains at least four resident macrophage populations and that LYVE1hi mesothelial macrophages drive tumor growth independently of the omentum.

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.