Guo et al. used machine learning-based self-correlation analysis and multiplex IF staining to compare tumor-free tumor-draining lymph node (TDLN) samples from patients with "cold" versus "hot" triple-negative breast cancers. In TDLNCold samples, mature dendritic cells, driven by the increased IL-4 production by mast cells, preferentially primed CD4+ T cells toward a Th2 phenotype. The Th2 polarization within TDLNCold was associated with increased Th2/Th1 ratios, upregulated tissue repairing and fibrosis-related genes, and reduced immune infiltration in paired cold tumors.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, C
Author Info: (1) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (2) 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. (3) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. International Cancer Center, Shenzhen University Medical School, 518060, Shenzhen, Guangdong, China. (4) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (5) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (6) Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA. (7) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. Genomics Core, Cleveland Clinic, Cleveland, OH, 44106, USA. (8) Mork Family Department of Chemical Engineering & Material Science, University of Southern California, Los Angeles, CA, 90089, USA. (9) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. (10) Department of Medical Oncology, City of Hope, Duarte, CA, 91010, USA. (11) Department of Pathology, City of Hope, Duarte, CA, 91010, USA. Pathology Laboratory Administration, Los Angeles General Medical Center, Los Angeles, CA, 90033, USA. (12) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. Owkin, Inc., New York, NY, 10003, USA. (13) Department of Pathology, City of Hope, Duarte, CA, 91010, USA. (14) Department of Pathology, City of Hope, Duarte, CA, 91010, USA. (15) Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA. plee@coh.org.
