Abstract
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.
Highlights
Cancer cells can enter lymphatic vessels and travel to lymph nodes (LN) where they can form LN metastasis
A–E, Normal LN tissue sections probed with antibodies against CD90, PDPN, CD3, CD21, CD146, and collagen were examined by fluorescence microscopy to assess the phenotype of human LN fibroblastic reticular cells (FRC)
Despite the substantial changes observed in the architecture of melanomainfiltrated LNs (MILN), we demonstrated the presence of three distinct cancer-associated stromal cells (SC) populations within the CD90þ fraction, similar to those identified in normal LNs; these included CD34þ SCs, FRCs (CD34ÀPDPNþ), and pericytes (CD34ÀPDPNÀCD146þ; Fig. 5A)
Summary
Cancer cells can enter lymphatic vessels and travel to lymph nodes (LN) where they can form LN metastasis. In normal LNs, different populations of stromal cells (SC) of mesenchymal origin, including fibroblastic reticular cells (FRC), follicular dendritic cells (FDC), and marginal reticular cells (MRC), construct an elaborate LN architecture, supporting various LN functions [1,2,3,4,5,6]. FRCs produce factors that support T-cell survival and form a conduit system delivering small antigens and signaling molecules to immune cells within the LN [7, 8]. Following tumor infiltration into LNs, tumorsubverted SCs contribute to tumor progression by mechanisms like the production of tumor growth factors, stimulation of angiogenesis, and suppression antitumor immune responses [9,10,11]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).
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