Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
Irell & Manella Graduate School of Biological Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
Nat Commun. 2024 Oct 4;15(1):8592. doi: 10.1038/s41467-024-52577-y.
Tumor draining lymph nodes (TDLN) represent a key component of the tumor-immunity cycle. There are few studies describing how TDLNs impact lymphocyte infiltration into tumors. Here we directly compare tumor-free TDLNs draining "cold" and "hot" human triple negative breast cancers (TDLN and TDLN). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLN. Two gene pairs (TBX21/GATA3-CXCR1) with opposite correlations suggest preferential priming of T helper 2 (Th2) cells by mature dendritic cells (DC) within TDLN. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLN versus TDLN. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLN. Downstream, Th2-associated fibrotic TME is found in paired cold tumors with increased Th2/T-helper-1-cell (Th1) ratio, upregulated fibrosis growth factors, and stromal enrichment of cancer associated fibroblasts. These findings are further confirmed in a validation cohort and public genomic data. Our results reveal a potential role of IL4 MCs within TDLNs, associated with Th2 polarization and reduced immune infiltration into tumors.
肿瘤引流淋巴结 (TDLN) 是肿瘤免疫循环的关键组成部分。目前很少有研究描述 TDLN 如何影响淋巴细胞浸润肿瘤。在这里,我们直接比较了无肿瘤 TDLN 引流的“冷”和“热”人类三阴性乳腺癌 (TDLN 和 TDLN)。我们使用基于机器学习的免疫基因表达自相关分析,发现 TDLN 内存在不平衡的腔内调节。两个具有相反相关性的基因对 (TBX21/GATA3-CXCR1) 提示成熟树突状细胞 (DC) 优先在 TDLN 内启动辅助性 T 细胞 2 (Th2) 细胞。这通过多重免疫荧光染色得到了验证,鉴定出 TDLN 中比 TDLN 更多的成熟-DC-Th2 空间簇。与这种 Th2 启动偏好相关的是,在 TDLN 的窦区发现了更多产生 IL4 的肥大细胞 (MC)。下游,在配对的冷肿瘤中发现了与 Th2 相关的纤维化 TME,其 Th2/T-helper-1-cell (Th1) 比值增加,纤维化生长因子上调,以及癌症相关成纤维细胞在基质中的富集。这些发现进一步在验证队列和公共基因组数据中得到了证实。我们的研究结果揭示了 TDLN 内 IL4 MC 的潜在作用,与 Th2 极化和肿瘤内免疫浸润减少有关。