Tumor draining lymph nodes connected to cold triple-negative breast cancers are characterized by Th2-associated microenvironment

Weihua Guo, Jiayi Tan, Lei Wang, Colt A. Egelston, Diana L. Simons, Aaron Ochoa, Min Hui Lim, Lu Wang, Shawn Solomon, James Waisman, Christina H. Wei, Caroline Hoffmann, Joo Song, Daniel Schmolze and Peter P. Lee ()
Additional contact information
Weihua Guo: Beckman Research Institute, City of Hope
Jiayi Tan: Beckman Research Institute, City of Hope
Lei Wang: Beckman Research Institute, City of Hope
Colt A. Egelston: Beckman Research Institute, City of Hope
Diana L. Simons: Beckman Research Institute, City of Hope
Aaron Ochoa: City of Hope Comprehensive Cancer Center
Min Hui Lim: Beckman Research Institute, City of Hope
Lu Wang: University of Southern California
Shawn Solomon: Beckman Research Institute, City of Hope
James Waisman: City of Hope
Christina H. Wei: City of Hope
Caroline Hoffmann: Beckman Research Institute, City of Hope
Joo Song: City of Hope
Daniel Schmolze: City of Hope
Peter P. Lee: Beckman Research Institute, City of Hope

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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 (TDLNCold and TDLNHot). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLNCold. Two gene pairs (TBX21/GATA3-CXCR1) with opposite correlations suggest preferential priming of T helper 2 (Th2) cells by mature dendritic cells (DC) within TDLNCold. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLNCold versus TDLNHot. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLNCold. 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.

Date: 2024
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DOI: 10.1038/s41467-024-52577-y

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