RESUMO
The role of hypoxia in the tumor microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains unclear. Here, we generated a comprehensive atlas of the entire tumor microenvironment and delineated the multifaceted cell-cell interactions to decipher hypoxia-induced pro-tumor immune suppression. We discovered hypoxia is significantly associated with iCCA progression via the activation of HIF1A expression. Moreover, hypoxia-dependent PPARγ-mediated fatty acid oxidation in APOE+ TAMs promoted M2 macrophage polarization by activating the HIF1A-PPARG-CD36 axis. These polarized APOE+ TAMs recruited Treg cell infiltration via the CCL3-CCR5 pair to form an immunosuppressive microenvironment. APOE+ TAMs tended to co-localize spatially with Treg cells in the malignant tissue based on spatial transcriptome data and immunofluorescence analysis results. We identified tumor-reactive CXCL13+ CD8-PreTex with specific high expression of ENTPD1 and ITGAE, which acted as precursors of CD8-Tex and had higher cytotoxicity, lower exhaustion, and more vigorous proliferation. Consequently, CXCL13+ CD8-PreTex functioned as a positive regulator of antitumor immunity by expressing the pro-inflammatory cytokines IFNG and TNF, associated with a better survival outcome. Our study reveals the mechanisms involved in hypoxia-induced immunosuppression and suggests that targeting precursor-exhausted CXCL13+CD8+ T cells might provide a pratical immunotherapeutic approach.
RESUMO
The role of tumor-resident microbiota in modulating tumor immunity remains unclear. Here, we discovered an abundance of intra-tumoral bacteria, such us E.coli, residing and resulting in Colorectal cancer liver metastasis (CRLM). E.coli enhanced lactate production, which mediated M2 macrophage polarization by suppressing nuclear factor-κB -gene binding (NF-κB) signaling through retinoic acid-inducible gene 1 (RIG-I) lactylation. Lactylation of RIG-I suppressed recruitment of NF-κB to the Nlrp3 promoter in macrophages, thereby reducing its transcription. This loss of Nlrp3 affected the immunosuppressive activities of regulatory T cells (Tregs) and the antitumor activities of and CD8+ T cells. Small-molecule compound screening identified a RIG-I lactylation inhibitor that suppressed M2 polarization and sensitized CRLM to 5-fluorouracil (5-FU). Our findings suggest that tumor-resident microbiota may be a potential target for preventing and treating CRLM.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , NF-kappa B , Neoplasias Colorretais/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/imunologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/microbiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Animais , Humanos , Camundongos , NF-kappa B/metabolismo , Microbiota/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Escherichia coli , Linfócitos T Reguladores/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Transdução de SinaisRESUMO
Although targeting the tumor metabolism is performed in cooperation with immunotherapy in the era of precision oncology, ignorance of immune cells' metabolism has resulted in unstable antitumor responses. Tumor-infiltrating regulatory T cells (TI-Tregs) are unique, overcoming the hypoxic, acidic, and nutrient-deficient tumor microenvironments (TMEs) and maintaining immunosuppressive functions. However, secondary autoimmunity caused by systemic Treg depletion remains the 'Sword of Damocles' for current Treg-targeted therapies. In this opinion piece, we propose that metabolically reprogrammed TI-Tregs might represent an obstacle to cancer therapies. Indeed, metabolism-based Treg-targeted therapy might provide higher selectivity for clearing TI-Tregs than traditional kinase/checkpoint inhibitors and chemokine/chemokine receptor blockade; it might also restore the efficacy of targeting the tumor metabolism and eliminate certain metabolic barriers to immunotherapy.