01
Cancer cells impair monocyte-mediated T cell stimulation to evade immunity
Anais Elewaut. et al.
Nature. 2024
Inflammatory monocytes activate CD8+ T cells by acquiring and presenting peptide-MHC-I complexes from tumor cells through a mechanism known as "cross-dressing." In untreated (NTT) tumors, tumor-specific CD8+ T cells and inflammatory monocytes form multicellular hubs. This interaction leads to Nur77 upregulation, a marker of TCR activation, in over 80% of T cells. However, in resistant tumors, this percentage drops significantly to around 20%. These findings underscore the critical role of inflammatory monocytes in maintaining T-cell activation. Further investigation revealed that hyperactivation of the MAPK signaling pathway in tumor cells is the main factor suppressing this mechanism. Specifically, abnormal MAPK signaling reduces the production of IFN-I and increases PGE2 secretion. PGE2 not only directly impairs the function of inflammatory monocytes but also disrupts their interaction with T cells, significantly weakening T-cell reactivation. In the early stages of tumor development, inflammatory monocytes recruit other immune cells by releasing chemokines. However, in later stages, their role shifts towards direct antigen presentation and local T-cell activation. Enhancing IFN-I levels and blocking PGE2 production can effectively restore monocyte functionality, bolstering T-cell-mediated anti-tumor immunity. In resistant tumors lacking PGE2, T-cell numbers triple, showing increased proliferation and effector function. Additionally, overexpression of IRF3/7 genes to restore IFN-I production leads to increase in T-cell infiltration and over 50% tumor volume reduction. A combined approach using COX inhibitors and IFN-I agonists significantly improves the tumor microenvironment and enhances T-cell effector function. In mouse models, this combination therapy quadruples intratumoral CD8+ T-cell numbers and markedly inhibits tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of PGE2 synthesis-related genes effectively reduces PGE2 levels and restores inflammatory monocyte activity.
DOI: 10.1038/s41586-024-08257-4
02
Benjamin Y Lu. et al.
Nat Immuno. 2024
The researchers analyzed tumor tissues and peripheral blood samples from 17 melanoma patients undergoing immunotherapy. By combining scRNA-seq and TCR sequencing, the researchers assessed which T cells in peripheral blood were tumor-reactive. Initial screening revealed that tumor-reactive T cells were predominantly CD8+ T cells, originating from clonal expansion. Further classification based on activation states showed that circulating tumor-reactive T cells commonly exhibited high expression of multiple NK cell-related genes (e.g., NKG7, KLRD1) and genes encoding the KIR protein family. After comparing key gene and protein expression profiles, the researchers confirmed that these circulating KIR+ CD8+ T cells closely resembled previously described CD8+ regulatory T cells. In co-culture experiments, these KIR+ CD8+ T cells selectively suppressed the function (and reduced the proportion) of other tumor-reactive CD8+ T cells without affecting CD4+ T cells.In paired tumor tissue samples, T cells with gene characteristics highly consistent with the peripheral blood KIR+ CD8+ T cells were identified. Unlike the exhausted state induced by chronic antigen stimulation, these intratumoral KIR+ CD8+ T cells may exert immunosuppressive functions within the tumor microenvironment. Using tumor neoantigen data from the patients, the researchers constructed a tumor antigen peptide library. They then utilized TCR-transduced cell lines to demonstrate that KIR+ CD8+ T cells were tumor-antigen specific and could be activated by tumor-derived antigens. Since KIR+ CD8+ T cells suppress the functions of CD8+ T cells actively involved in anti-tumor immunity, their presence is likely detrimental to patient prognosis. Survival data from melanoma patients supported this hypothesis: patients with higher frequencies of peripheral blood KIR+ CD8+ T cells had significantly lower three-year overall survival (OS) rates, especially among those with immunotherapy resistance. Thus, the frequency of KIR+ CD8+ T cells could serve as a prognostic biomarker. Moreover, KIR+ CD8+ T cells may play a crucial role in driving immunotherapy resistance, warranting further investigation.
DOI: 10.1038/s41590-024-02023-4
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