Tumor-driven matrix invasion by infiltrating lymphocytes: involvement of the alpha1 integrin I-domain.
Here we show that tumor cells (TC) from renal cancers regulate the migratory properties of autologous tumor-infiltrating lymphocytes (TIL), enhancing their ability to invade the extracellular matrix. A similar effect is exerted by human recombinant macrophage chemotactic protein 1 (MCP-1) and IL-8, chemokines known to increase T lymphocyte migration both across vascular endothelium and subendothelial matrix. We found that TC freshly derived from renal cell carcinoma surgical specimens constitutively secrete both IL-8 and MCP-1 and that TIL express both specific receptors. TIL matrix invasion elicited by TC is inhibited by the addition of neutralizing antisera specific for IL-8 and MCP-1, demonstrating the direct relationship between chemokine release by TC and TIL invasion. Of note, TIL invasion of the extracellular matrix requires the alpha1 integrin, which acts through its I-domain that is upregulated upon culture with MCP-1 and IL-8. Collectively, these findings suggest that TC may actively recruit TIL via the release of chemotactic factors that enhance an alpha1 integrin-mediated pathway of matrix invasion.
Laboratory of Tumor Immunology, Scientific Institute of San Raffaele, Milan, Italy.
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Ferrero
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Fabbri
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Poggi
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Galati
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Bernasconi
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Zocchi
D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004727:Endothelium / Q000276:immunology / Q000473:pathology; D005109:Extracellular Matrix / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D039423:Integrin alpha1; D016209:Interleukin-8 / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology
D015703:Antigens, CD; D018932:Chemokine CCL2; D039423:Integrin alpha1; D016209:Interleukin-8