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2025年
Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism
Abstarct
CD8+ T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as T cell exhaustion, after persistent T cell receptor stimulation in the tumor microenvironment (TME). Exhausted T (Tex) cells are characterized by upregulation of coinhibitory molecules and reduced polyfunctionality. T cells in the TME experience an immunosuppressive metabolic environment via reduced levels of nutrients and oxygen and a buildup of lactic acid. Here we show that terminally Tex cells uniquely upregulate Slc16a11, which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion of MCT11 in T cells reduced lactic acid uptake by Tex cells and improved their effector function. Targeting MCT11 with an antibody reduced lactate uptake specifically in Tex cells, which, when used therapeutically in tumor-bearing mice, resulted in reduced tumor growth. These data support a model in which Tex cells upregulate MCT11, rendering them sensitive to lactic acid present at high levels in the TME.
Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis
Abstarct
Red blood cells, or erythrocytes, are formed through the differentiation of hematopoietic stem cells (HSCs). Looking at two situations of erythropoietic stress caused by an increased demand to produce red bloods, Phan et al. found that the transcripts of genetic elements known as retrotransposons increased in HSCs. Blocking reverse transcription or genetic deletion of the cellular machinery used to sense and respond to nucleic acids in HSCs decreased blood cell numbers in pregnant mice, but not in nonpregnant mice. This work suggests that retrotransposon transcripts use these innate immune molecules to promote hematopoiesis and erythropoiesis in situations of stress rather than homeostasis, and similar mechanisms might exist in humans. —Sarah H. Ross
Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity
Abstract
Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (\(\rm{T_{RM}}\)) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated \(\rm{T_{RM}}\) reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring \(\rm{T_{RM}}\) in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced \(\rm{T_{RM}}\) restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.