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Dvorakova T, et al.
Nat Commun. 2024.
Adoptive cell therapy has been effective against blood cancers but faces challenges in treating solid tumors due to the suppressive tumor microenvironment (TME). The hypoxia-inducible factor (HIF) family, known for regulating T-cell metabolism and function, has not been extensively studied in the context of adoptive cell transfer for activated CD8 T cells. In this study, CRISPR-Cas9 technology is used to delete prolyl hydroxylase domain-containing enzymes (PHD) 2 and 3 in differentiated and activated CD8 T cells, stabilizing HIF-1 signaling. This deletion leads to increased T-cell activation and effector functions, which is HIF-1α dependent and results in enhanced glycolytic flux. The enhanced performance of CD8 T cells improves tumor response to adoptive T cell therapy in mice, even in tumor models previously resistant to immunotherapy. These results suggest potential for improving CD8 T-cell therapies and overcoming immune suppression in the TME.
DOI: 10.1038/s41467-024-51782-z
02
SPP1+ TAM Regulates the Metastatic Colonization of CXCR4+ Metastasis-Associated Tumor Cells by Remodeling the Lymph Node Microenvironment
Sci Adv. 2024.
Lymph node metastasis is a critical initial step in the progression to distant metastasis and a major contributor to the high mortality rates observed in patients with oral squamous cell carcinoma (OSCC). Despite its significance, the mechanisms driving lymph node metastasis in OSCC are not fully understood. In this study, the transcriptomes of 56,383 single cells from six OSCC patients' paired tissues were analyzed, revealing that CXCR4+ epithelial cells, identified as highly malignant disseminated tumor cells (DTCs), are prone to metastasize to lymph nodes.Importantly, the research identified a unique subset of tumor-associated macrophages (TAMs) defined by their exclusive expression of the phosphoprotein 1 (SPP1). These SPP1-expressing TAMs are suggested to play a role in reshaping the metastatic lymph node microenvironment. They may activate fibroblasts and contribute to T cell exhaustion through SPP1-CD44 and CD155-CD226 ligand-receptor interactions, which could promote the colonization and proliferation of DTCs.This study has enhanced the understanding of the metastatic tumor microenvironment (TME) in OSCC and laid the groundwork for developing personalized treatment strategies for patients with metastatic OSCC.
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