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In a very interesting article, Rosenberg et al. (1) reported that presence of tumor Ag-specific CD8+ T cells can not by themselves be used as a “surrogate marker” for vaccine efficacy. They also mentioned that their data regarding “tumor escape” were inconclusive. They showed that some recurrent melanoma tumors expressed HLA class I Ag and the Ag, gp100, to which CD8+ T cells were present. Lack of data in their report regarding the status of escape mechanisms in recurrent tumors may result in underestimation of the role of tumor-specific CD8+ T cells and IFN-γ against primary tumors. We have found that emergence of the recurrent mammary tumors is due to epigenetic changes in the primary tumors rendering them resistant to a specific pathway of CTL response (2). Unlike primary mouse mammary carcinomas (MMCs), a relapsed phenotype of these tumors, the neu antigen-negative variant (ANV) (2), showed decreased expression of the IFN-γ downstream signaling protein, STAT-1, despite similar levels of expression of IFN-γR in both tumors (Fig. 1). On the other hand, relapsed tumors expressed higher levels of Fas, rendering them susceptible to Fas-mediated killing rather than IFN-γ-mediated killing. Furthermore, expression of antiapoptotic Sphingosine kinase (Sphk) 1 was higher in relapsed ANV than that in primary mouse mammary carcinoma tumors whereas expression of proapoptotic Spkh2 was lower in ANV (Fig. 2). Although IFN-γ can be effective against primary tumors (3 3) and may fail to kill some relapsed tumors, CD8+ T cells may still be effective against relapsed tumor via Fas-Fas ligand-mediated apoptosis. In addition, antitumor efficacy of IFN-γ, Fas ligand, granzyme B, and other pathways of T cell-mediated tumor killing depends on the status of tumor escape.

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