TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion
Journal for ImmunoTherapy of Cancer. 2024 The study by Debesset et al. investigates the role of tumor necrosis factor α receptor 2 (TNFR2) blockade in enhancing the antitumor immune response in pancreatic ductal adenocarcinoma (PDAC). PDAC is highly resistant to standard chemotherapy and immunotherapy, with regulatory T cells (Tregs) contributing to immunosuppression. The researchers hypothesized that inhibiting TNFR2 could shift the balance between Tregs and effector T cells, thereby enhancing antitumor responses. Using single-cell analysis data from 24 PDAC patients, the team identified elevated TNFR2 expression in Tregs, myeloid cells, and endothelial cells, with lower levels in tumor cells. They employed orthotopic and immunocompetent mouse models of PDAC to analyze the immune environment before and after anti-TNFR2 monoclonal antibody (mAb) treatment. The results showed that the anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8+ T cells. However, the treatment alone had limited efficacy in activating CD8+ T cells and only slightly reduced tumor growth. The combination of anti-TNFR2 mAb with an agonistic anti-CD40 mAb led to stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice. The study suggests that combining a CD40 agonist with a TNFR2 antagonist could be a promising therapeutic strategy for PDAC patients. This research highlights the potential of TNFR2 as a new target in the therapeutic arsenal for treating tumors refractory to immune checkpoint inhibitors, offering valuable insights into the heterogeneity of PDAC and the role of TNFR2 in the antitumor immune response.DOI: 10.1136/jitc-2024-008898
Single-cell RNA sequencing reveals immune microenvironment niche transitions during the invasive and metastatic processes of ground-glass nodules and part-solid nodules in lung adenocarcinoma
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Ren, YF. et al.
The study by Ren et al. investigates the immune microenvironment in lung adenocarcinoma (LUAD) with a focus on ground-glass nodules (GGN) and part-solid nodules (PSN). Using single-cell RNA sequencing, the team analyzed tumor tissues from LUAD patients at different stages, including minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (IAC), and metastatic lung cancer (MLC). They found significant changes in tumor-associated macrophages (TAMs), particularly CXCL9+ and TREM2+ TAMs, which play crucial roles in LUAD progression. GGN-LUAD showed stronger immune responses with increased interactions between CXCL9+ TAMs and CD8+ T cells during early stages, while PSN-LUAD exhibited more interactions between TREM2+ TAMs and tumor cells in later stages. The study highlights the IFN-γ/STAT1 pathway's role in regulating CXCL9+ TAM activation and suggests that balancing CXCL9+ and TREM2+ TAMs could improve immunotherapy outcomes. This research provides insights into LUAD's heterogeneity and potential therapeutic targets.
DOI: 10.1186/s12943-024-02177-7
Editor & Reviewer: Congci Yu
