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; Peter P Lee

doi:10.1038/s41467-024-52577-y

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

Nat Commun. 2024 Oct 4;15(1):8592. doi: 10.1038/s41467-024-52577-y.

Authors

Weihua Guo¹, Jiayi Tan^{1

2}, Lei Wang^{1

3}, Colt A Egelston¹, Diana L Simons¹, Aaron Ochoa⁴, Min Hui Lim^{1

5}, Lu Wang⁶, Shawn Solomon¹, James Waisman⁷, Christina H Wei^{8

9}, Caroline Hoffmann^{1

10}, Joo Song⁸, Daniel Schmolze⁸, Peter P Lee¹¹

Affiliations

¹ Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
² Irell & Manella Graduate School of Biological Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
³ International Cancer Center, Shenzhen University Medical School, 518060, Shenzhen, Guangdong, China.
⁴ Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
⁵ Genomics Core, Cleveland Clinic, Cleveland, OH, 44106, USA.
⁶ Mork Family Department of Chemical Engineering & Material Science, University of Southern California, Los Angeles, CA, 90089, USA.
⁷ Department of Medical Oncology, City of Hope, Duarte, CA, 91010, USA.
⁸ Department of Pathology, City of Hope, Duarte, CA, 91010, USA.
⁹ Pathology Laboratory Administration, Los Angeles General Medical Center, Los Angeles, CA, 90033, USA.
¹⁰ Owkin, Inc., New York, NY, 10003, USA.
¹¹ Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. plee@coh.org.

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 (TDLN_Cold and TDLN_Hot). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLN_Cold. 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_Cold. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLN_Cold versus TDLN_Hot. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLN_Cold. 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.

MeSH terms

Dendritic Cells / immunology
Female
Gene Expression Regulation, Neoplastic
Humans
Lymph Nodes* / immunology
Lymph Nodes* / pathology
Lymphocytes, Tumor-Infiltrating / immunology
Mast Cells / immunology
Mast Cells / metabolism
Th1 Cells / immunology
Th2 Cells* / immunology
Triple Negative Breast Neoplasms* / genetics
Triple Negative Breast Neoplasms* / immunology
Triple Negative Breast Neoplasms* / pathology
Tumor Microenvironment* / genetics
Tumor Microenvironment* / immunology

Abstract

MeSH terms

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