A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death.
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-alpha 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 TNFalpha, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) 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-1alpha) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.
Mellado
M
M
Department of Immunology and Oncology, Centro Nacional de Biotecnología, CSIC/UAM, Campus de Cantoblanco, E-28049, Madrid, Spain. cmartineza@cnb.uam.es
de Ana
A M
AM
Moreno
M C
MC
Martínez
C
C
Rodríguez-Frade
J M
JM
D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D018925:Chemokines / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology; D014407:Tumor Cells, Cultured
D018925:Chemokines; D003574:Cytochrome c Group; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases