A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death

M Mellado, AM de Ana, MC Moreno, C Martı́nez-A… - Current Biology, 2001 - cell.com
M Mellado, AM de Ana, MC Moreno, C Martı́nez-A, JM Rodrıguez-Frade
Current Biology, 2001cell.com
The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses
to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1].
Several mechanisms may account for this subversion, including the triggering of tolerance to
tumor antigens [2, 3], TGF-α or IL-10 production, downregulation of MHC molecules, or
upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL
expression to protect themselves against tumor-infiltrating lymphocytes (TIL)[4, 5]. Here, we …
Abstract
The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1]. Several mechanisms may account for this subversion, including the triggering of tolerance to tumor antigens [2, 3], TGF-α or IL-10 production, downregulation of MHC molecules, or upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL expression to protect themselves against tumor-infiltrating lymphocytes (TIL) [4, 5]. Here, we show another, chemokine-dependent mechanism by which melanoma tumor cells shield themselves from immune reactions. Melanoma-inducible CCL5 (RANTES) production by infiltrating CD8 cells activates an apoptotic pathway in TIL involving cytochrome c release into the cytosol and activation of caspase-9 and -3. This process, triggered by CCL5 binding to CCR5, is not mediated by TNFα, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1α) and CCL4 (MIP-1β) also trigger TIL cell death, nor is it limited to melanoma cells, as it also operates in activated primary T lymphocytes. The model assigns a role to the CXC chemokine CXCL12 (SDF-1α) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.
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