Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90⁺ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90⁺ podoplanin⁺ CD105⁺ CD146⁺ CD271⁺ VCAM-1⁺ ICAM-1⁺ α-SMA⁺) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90⁺ CD34⁺ CD105⁺ CD271⁺) represents a novel population of CD34⁺ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90⁺ CD146⁺ CD36⁺ NG2^- pericytes in the walls of high endothelial venules and other small vessels, and CD90⁺ CD146⁺ NG2⁺ CD36^- pericytes in the walls of larger vessels. Distinguishing between these CD90⁺ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.

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