ABSTRACT
Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8+ T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8+ T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth. SIGNIFICANCE: This study suggests that ablation of TET2+ from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , DNA-Binding Proteins/deficiency , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Melanoma, Experimental/immunology , Proto-Oncogene Proteins/deficiency , Adoptive Transfer/methods , Animals , Chromatin/metabolism , DNA Demethylation , DNA-Binding Proteins/genetics , Dioxygenases , Disease Models, Animal , Epigenesis, Genetic , Gene Deletion , Gene Silencing , Immune Checkpoint Inhibitors/therapeutic use , MAP Kinase Kinase Kinases , Melanoma, Experimental/metabolism , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Ovalbumin/immunology , Perforin/metabolism , Proto-Oncogene Proteins/genetics , Sequence Analysis, RNA , Transcription Factors/metabolism , Tumor Microenvironment/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Intracerebral hemorrhage (ICH) is a particularly devastating event both because of the direct injury from space-occupying blood to the sequelae of the brain exposed to free blood components from which it is normally protected. Not surprisingly, the usual metabolic and energy pathways are overwhelmed in this situation. In this review article, we detail the complexity of red blood cell degradation, the contribution of eryptosis leading to hemoglobin breakdown into its constituents, the participants in that process, and the points at which injury can be propagated such as elaboration of toxic radicals through the metabolism of the breakdown products. Two prominent products of this breakdown sequence, hemin, and iron, induce a variety of pathologies including free radical damage and DNA breakage, which appear to include events independent from typical oxidative DNA injury. As a result of this confluence of damaging elements, multiple pathways of injury, cell death, and survival are likely engaged including ferroptosis (which may be the same as oxytosis but viewed from a different perspective) and senescence, suggesting that targeting any single cause will likely not be a sufficient strategy to maximally improve outcome. Combination therapies in addition to safe methods to reduce blood burden should be pursued.
