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Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers.

Human regulatory T cells (T regs ) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of T regs for cancer therapy without affecting immune homeostasis. Identifying pathways that may distinguish tumor-restricted T regs is important, yet the transcriptional programs that control intratumoral T reg gene expression, and that are distinct from T regs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4 + T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC) and those in nontumor tonsil tissues and peripheral blood from healthy donors. We identified a subpopulation of activated T regs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR + T regs ) that is highly enriched in the tumor microenvironment (TME) compared with nontumor tissue and the periphery. TNFR + T regs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR + T regs . CRISPR-Cas9-mediated BATF knockout in human activated T regs in conjunction with bulk RNA sequencing, immunophenotyping, and in vitro functional assays corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated T regs . Last, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral T regs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral T regs , highlighting potential opportunities for therapeutic intervention in cancer without affecting immune homeostasis.

Competing Interests: Conflict-of-Interest Disclosures: Jessica Castner discloses receiving grants and fees from the National Institutes of Health, fees from the Emergency Nurses Association, and serving as co-chair of the American Thoracic Society’s Health Policy Committee on Terrorism and Inhalation Disasters section. Barbara Evans discloses receiving grants from the National Institutes of Health. Steven Lin discloses serving as VP of Health Sciences for Codex Health, where he is a paid consultant; and receiving grants administered through Stanford University from Amazon, American Academy of Family Physicians, American Board of Family Medicine, Center for Professionalism and Value in Health Care, DeepScribe, Google Health, Omada Health, Predicta Med, Quadrant Technologies, Soap Health, Society of Teachers of Family Medicine, UCSF, and Verily. Kenneth Mandl discloses that his laboratory receives sponsored research funding from Quest Diagnostics; and that Boston Children’s Hospital receives corporate philanthropic support for his laboratory from SMART Advisory Committee members, which include the American Medical Association, BMJ Group, Eli Lilly and Company, Google Cloud, Hospital Corporation of America, Microsoft, Optum, Cambia Health Solutions, Quest Diagnostics, and Humana. Mark Sendak discloses that he is co-inventor of technology licensed from Duke University to Cohere Med, Inc and Clinetic, Inc.; and that he holds equity in Clinetic, Inc. Carmel Shachar discloses that she is a member of Advarra’s Institutional Research Board.

Competing Interests: Conflict-of-Interest Disclosures: Dr. Michener discloses serving as Principal Investigator for the Practical Playbook™ and as consultant for HHS, OAHS, NIH, CDC, HRSA, UC Davis, and Rockefeller University.

Intensive care units (ICUs) lack both standardized performance indicators to better understand the effectiveness of interventions and uniform platforms to present these indicators. The goal of this study was to identify ICU metrics meaningful to stakeholders to help guide the development of a local visualization dashboard. Individual ICU directors were interviewed to collate their input on metrics important to their units. These qualitative data were used to develop a dashboard draft, after which the authors surveyed 20 stakeholders from different hospital departments for feedback on its content and structure. The varied survey results reinforced the inherent difficulties of adapting previously developed measurement tools while also selecting ICU performance measures that are simultaneously widely accepted yet relevant to local practice. These results also call attention to the importance of interdisciplinary input in quality dashboard development, thereby enabling more successful implementation and utilization for ICU quality improvement., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)