Biomarkers of response to immunotherapy in lung cancer remain elusive. Valencia et al. identify DSTYK as a cancer cell–intrinsic modulator of sensitivity to CD8+ T cell activity. By regulating the mTOR pathway and stimulating protective autophagy, DSTYK blunts TNF-α–mediated killing by T cells, thereby limiting the efficacy of immunotherapy.
The study of sex differences in neurodegeneration can reveal treatment targets tailored for women and men. Sex differences in neurodegeneration are reviewed, focusing on sex chromosome effects in the context of declining levels of sex hormones during aging.
Brief Definitive Reports
c-MAF, highly expressed in villus small intestinal enterocytes, coordinates transcriptional programs for nutrient absorption. Enterocyte-specific c-MAF inactivation impairs dietary lipid handling but also leads to tuft cell expansion and adaptive gut lengthening, revealing crosstalk between enterocytes and tuft cells during intestinal adaptation.
Intestinal epithelial c-Maf expression determines enterocyte differentiation and nutrient uptake in mice
This study identifies c-Maf as an enterocyte-specific transcription factor within the small intestinal epithelium. c-Maf governs the spatial and functional specialization of enterocytes, especially gene programs controlling intestinal nutrient absorption. Thus, epithelial c-Maf deletion results in impaired enterocyte maturation, nutrient uptake, and alterations of the immune system and microbiota.
The miR-181 family is downregulated in IECs from human IBD patients and in mice with colitis, a process that is critical for the development of severe colonic inflammation as this microRNA family promotes IEC proliferation and re-epithelialization by potentially enhancing Wnt signaling.
NK cells play a critical role in immune surveillance, yet negative regulators of their maturation and function are poorly characterized. Imianowski et al. show that the transcriptional repressor BACH2 restricts NK cell maturation and anti-tumor function, with implications for immunotherapeutic development.
An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through PD-1-cis delivery
The authors engineer an anti-PD-1–concealed sIL-15 fusion protein (αPD-1-IL-15-R), eliciting extraordinary antitumor immunity with negligible toxicity. αPD-1-IL-15-R largely expands tumor-specific CD8+T for effective tumor rejection through cis-delivery and further controls metastasis.
Valencia et al. show DSTYK, a dual serine/threonine and tyrosine kinase, altered in lung cancer and associated with poor clinical outcome. DSTYK controls cellular processes encompassing cytoprotective autophagy and mitochondrial fitness and its ablation sensitizes cancer cells to T cell–mediated killing.
Inhibition of GABAA receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity
This study demonstrates that GABA regulates intestinal stem cell apoptosis through its A receptor in chemoradiotherapy-induced intestinal injury. FDA-approved GABAAR antagonist flumazenil may be a promising drug for reducing the gastrointestinal side effects brought by chemoradiotherapy.
Using mouse models overexpressing human TREM2 in microglia, this study shows that WT TREM2 expression reduces amyloid deposition and suppresses disease-associated microglia only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage.
Advanced age is the most critical risk factor for severe COVID-19. Using a newly established mouse model, Beer et al. demonstrate that the age-dependent exacerbation of disease is driven by a diminished innate and adaptive immune response due to impaired type I and type II interferon responses.
Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection in humans
Wang et al. analyze memory B cell and antibody responses in SARS-CoV-2 mRNA vaccines to breakthrough infections with Delta or Omicron BA.1 variants. Breakthrough infection after two or three doses of mRNA vaccination was comparable to three doses of vaccination in eliciting broad and potent memory B cells. The findings provide insights on broad and strain-specific memory responses after mRNA vaccination with Wuhan-Hu-1.
Neonatal HSV (nHSV) infections cause significant morbidity and mortality. This study demonstrates the efficacy of monoclonal antibody therapy via direct administration and AAV vectored expression. Antibodies administered either maternally or to mouse pups improve survival and time-dependent viral clearance.
Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47
In our study, we demonstrated the functional importance of intercellular mitochondria transfer to mediate bioenergetic profiles of recipient erythroblasts to facilitate their recovery from anemic stress. We also identified a subset of metabolically active erythroid populations with higher abundance of mitochondria transfer marked by CD47.
Correction: Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing