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Chemotherapy induces myeloid-driven spatially confined T cell exhaustion in ovarian cancer
Launonen. et al.
Cancer Cell. 2024
Their comprehensive multi-omics study, utilizing data from two extensive clinical cohorts at a large single-cell and spatial level, sheds light on the dynamic changes occurring within the tumor microenvironment (TME) in response to platinum-based chemotherapy. This approach highlights shifts in cell subtypes, states, spatial configurations, and complex molecular and cellular interactions. They observed that chemotherapy promotes T cell infiltration while also leading to localized T cell exhaustion in myeloid-rich areas. Notably, they identified the TIGIT-NECTIN2 interaction as a promising target for therapeutic strategies. Supporting this findings, previous research has documented increased infiltration of stromal and intraepithelial CD8+ T cells following neoadjuvant chemotherapy (NACT). While this increase suggests a potential response to PD1/PDL1 checkpoint inhibitors, earlier studies have shown mixed results, likely due to various immunosuppressive factors. Their t-CycIF analysis indicated no significant changes in macrophage infiltration post-NACT. Although bulk RNA-seq data indicated an increase in individual exhaustion markers due to chemotherapy, they found that exhaustion of tumor-recognizing CD8+ T cells was spatially restricted to M1-like myeloid neighborhoods. They introduce Myelonets—networks of interconnected myeloid cells—as a novel spatial structure that plays a crucial role in T cell-myeloid interactions and T cell exhaustion. This study enhances the understanding of myeloid-driven immunosuppression in chemotherapy-treated tumors, revealing that M1-driven exhaustion is localized within myelonets while M2-driven immunosuppression directly inhibits CD8+ T cell-tumor interactions. Furthermore, chemotherapy significantly increased interactions between TIGIT and CD96 on CD8+ T cells with NECTIN2 on macrophages. Given the high expression of TIGIT in exhausted CD8+ T cells within high-grade serous carcinoma (HGSC), targeting TIGIT presents a potential therapeutic avenue. Overall, their findings emphasize the importance of understanding the evolving tumor-immune-stromal interactions during chemotherapy to optimize strategies for enhancing anti-tumor immunity in HGSC.
DOI: 10.1016/j.ccell.2024.11.005
02
Chen Yang. et al.
Cancer Cell. 2024
The identification of tumor-initiating cells (TICs) primarily relies on cell surface markers. In this study, they conducted a thorough assessment of various TIC markers using multi-dimensional CITE-seq, which revealed CD49f—a previously overlooked surface marker in hepatocellular carcinoma (HCC)—as having significant advantages over other commonly used TIC markers. These advantages include enhanced identification of TICs, more consistent expression across different tumors, and greater specificity for tumor cells. Previous research in cancers like glioblastoma, breast cancer, and prostate cancer has demonstrated that CD49f can differentiate cell populations with increased tumorigenic potential. However, its most critical advantage—its superior ability to accurately identify TICs—was not fully appreciated in earlier studies. Moreover, CD49f is not only instrumental in identifying TICs but also plays direct pro-tumorigenic roles. Recent findings indicate that CD49f promotes leptomeningeal metastasis in breast cancer by binding to laminin on vascular surfaces. Consistent with this, they found higher ITGA6/CD49f expression in metastatic HCC compared to primary tumors, although the precise role of CD49f in HCC metastasis remains uncertain. This results show that CD49f-high TICs enhance the infiltration of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), including CD11b+Ly6g+ neutrophils, while decreasing CD8+ T cell infiltration. The recruitment of neutrophils by CD49f-high TICs occurs primarily through the CXCL2-CXCR2 axis. Additionally, the stemness-related transcription factor SOX9 may drive increased CXCL2 expression in these cells, indicating distinct roles for various stemness-related factors in immune evasion. While targeting CD49f directly poses risks due to its high expression in endothelial cells, targeting the associated marker CD155 may provide a more specific approach to eliminating CD49f-high TICs. The CD155/TIGIT pathway is recognized as a significant immunosuppressive mechanism beyond PD-L1/PD-1 interactions. This findings suggest that combining anti-CD155 with anti-PD-1 therapy could enhance tumor inhibition by targeting intra-tumor TICs and disrupting their interactions with neutrophils. However, this study has limitations; the mechanisms underlying functional changes in neutrophils remain unclear, and their focus on known immunosuppressive molecules may have overlooked less-studied surface markers involved in TIC immune evasion. Further research is needed to explore the complex regulatory networks within the TIC microenvironment and their unique mechanisms of immune evasion.
DOI: 10.1016/j.ccell.2024.10.008
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