Cancer-associated fibroblasts (CAFs) represent a functionally heterogenous population of activated fibroblasts that constitutes a major component of tumor stroma. Although CAFs have been shown to promote tumor growth and mediate resistance to chemotherapy, the mechanisms by which they may contribute to immune suppression within the tumor microenvironment (TME) in lung squamous cell carcinoma (LSCC) remain largely unexplored. Here, we identified a positive correlation between CAF and monocytic myeloid cell abundances in 501 primary LSCCs by mining TCGA datasets. We further validated this finding in an independent cohort using imaging mass cytometry and found a significant spatial interaction between CAFs and monocytic myeloid cells in the TME. To delineate the interplay between CAFs and monocytic myeloid cells, we used chemotaxis assays to show that LSCC patient-derived CAFs promoted recruitment of CCR2+ monocytes via CCL2, which could be reversed by CCR2 inhibition. Using a three-dimensional culture system, we found that CAFs polarized monocytes to adopt a myeloid-derived suppressor cell (MDSC) phenotype, characterized by robust suppression of autologous CD8+ T-cell proliferation and IFNγ production. We further demonstrated that inhibiting IDO1 and NADPH oxidases, NOX2 and NOX4, restored CD8+ T-cell proliferation by reducing reactive oxygen species (ROS) generation in CAF-induced MDSCs. Taken together, our study highlights a pivotal role of CAFs in regulating monocyte recruitment and differentiation and demonstrated that CCR2 inhibition and ROS scavenging abrogate the CAF-MDSC axis, illuminating a potential therapeutic path to reversing the CAF-mediated immunosuppressive microenvironment.

中文翻译：

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癌症相关的成纤维细胞通过在肺鳞状细胞癌中诱导产生ROS的单核MDSC来促进免疫抑制。

癌症相关的成纤维细胞（CAF）代表功能上异质的活化成纤维细胞，构成了肿瘤基质的主要成分。尽管已证明CAF可以促进肿瘤生长并介导对化疗的耐药性，但它们在肺鳞状细胞癌（LSCC）的肿瘤微环境（TME）内可能有助于免疫抑制的机制仍未阐明。在这里，我们通过挖掘TCGA数据集确定了501个原发性LSCC中CAF与单核细胞髓样细胞丰度之间的正相关。我们使用成像大规模细胞术在一个独立的队列中进一步验证了这一发现，并发现TME中CAF与单核细胞之间存在显着的空间相互作用。为了描述CAF与单核细胞之间的相互作用，我们使用趋化性试验显示，来自LSCC患者的CAF通过CCL2促进了CCR2 +单核细胞的募集，而CCR2抑制作用可以逆转这种募集。使用三维培养系统，我们发现CAFs极化单核细胞采取髓样抑制细胞（MDSC）表型，其特征是强烈抑制自体CD8 + T细胞增殖和IFNγ产生。我们进一步证明，抑制IDO1和NADPH氧化酶NOX2和NOX4可通过减少CAF诱导的MDSC中的活性氧（ROS）生成来恢复CD8 + T细胞增殖。综上所述，我们的研究突出了CAF在调节单核细胞募集和分化中的关键作用，并证明CCR2抑制和ROS清除消除了CAF-MDSC轴，