Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity

Defining a New Classification System for the Surgical Management of Neuroendocrine Tumor Liver Metastases

Although rarely curative, hepatic cytoreduction of neuroendocrine tumor liver metastases (NETLM) is associated with improved symptom control and prolonged survival. Preoperative 68Ga DOTATATE and gadoxetic acid-enhanced liver MRI can improve characterization of hepatic disease extent to improve surgical clearance, and resection of the primary tumor is associated with improved survival regardless of whether the liver metastases are treated. As parenchymal-sparing surgical techniques and the lowering of the debulking threshold have expanded the numbers of eligible NETLM patients for hepatic cytoreduction, we propose a new classification system to help guide surgical management. A multimodal approach that includes surgery, liver-directed therapies, and systemic therapies has improved outcomes and increased longevity for patients with well-differentiated metastatic NET

Stress and the Surgical Resident in the COVID-19 Pandemic.

ObjectiveThe COVID-19 pandemic has drastically transformed the healthcare community and medical education across the United States. The aim of this study was to evaluate the impact of COVID-19 on the surgical resident training experience, assess possible sources of stress or anxiety among surgery residents, and examine how patterns of anxiety vary by resident rank.DesignWe developed and disseminated a survey, which included the Generalized Anxiety Disorder 7-Item Scale (GAD-7), to all general and integrated plastic surgery residents in their clinical years of training at the University of California, San Francisco. Statistical analysis of the survey responses was performed using the Kruskal-Wallis or Wilcoxon rank sum test. Post-hoc analysis was performed using the Bonferroni-corrected Dunn test. Survey data were combined with aggregated duty hour information and operative case numbers from select hospitals for March and April of 2019 (historical baseline) and 2020.ResultsThe overall survey response rate was 73.7% (n = 73). With an estimated operative volume reduction of 63.3% for general surgery cases, over 90% of residents expressed concern about the decline in operative exposure. While the senior residents tended to work more shifts, they were not more likely to have higher risk perception scores for contracting COVID-19 nor higher anxiety levels about the possibility of contracting COVID-19. They were, however, significantly more likely to have high GAD-7 scores (≥ 10) when compared to interns (z = -2.82, p-adj = 0.014). Overall, residents were more concerned about the general health of loved ones than about their own risk of contracting COVID-19 (U = 3897.5, p < 0.01).ConclusionsWhile the work-related experiences of residents varied across a number of factors during the pandemic, residents tended to report similar sources of anxiety. Moving forward, surgical residency training programs will need to develop ways to optimize available surgical experiences and address the unique resident anxieties that an infectious pandemic presents

Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients