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Comment on "Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8⁺ T Cells in Patients with Melanoma"

Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298

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- 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- downstream signaling protein, STAT-1, despite similar levels of expression of IFN-R 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--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- 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-, Fas ligand, granzyme B, and other pathways of T cell-mediated tumor killing depends on the status of tumor escape.

View larger version (22K): [in this window] [in a new window]   FIGURE 1. Expression of IFN-Rs, STAT-1, and Fas in primary (MMC) and relapsed (ANV) tumors. Flow cytometry analysis using FITC-conjugated anti-IFN-R type 1 in MMC and ANV and RT-PCR analysis of lysates from ANV and MMC using primer pairs for Fas (5'-ATGCTGTGGATCTGGGCT-3' (sense) and 5'-TCACTCCAGACATTGTCC-3' (antisense)), STAT-1 (5'-CTTCTTCCTGAACCCCCCG-3' (sense) and 5'-CCCATCATTCCAGAGGCACAG-3' (antisense)) and -actin (5'-GTGGGCCGCTCTAGGCACCAA-3' (sense) and 5'-CTCTTTGATGTCACGCACGATTTC-3' (antisense)).

View larger version (47K): [in this window] [in a new window]   FIGURE 2. Expression of Sphk1 and Sphk2 in primary (MMC) and relapsed (ANV) tumors. RT-PCR analysis of lysates from MMC and ANV using primer pairs for Shpk1 (5'-CATGTGGTGGTGTTGTG-3' (sense), 5'-GTTATGGTTCTTCTGGAGG-3' (antisense)) and Sphk2 (5'-CCACCACTACTGCCAGT-3' (sense), 5'-CGTTCAGGCTTGCGGCT-3' (antisense)). Expression of -actin was determined as internal control.

This work was supported by National Institutes of Health grant CA104757.

References

1. Rosenberg, S. A., R. M. Sherry, K. E. Morton, W. J. Scharfman, J. C. Yang, S. L. Topalian, R. E. Royal, U. Kammula, N. P. Restifo, M. S. Hughes, et al 2005. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8⁺ T cells in patients with melanoma. J. Immunol. 175: 6169-6176. [Abstract/Free Full Text]
2. Manjili, M. H., H. Arnouk, K. L. Knutson, M. Kmieciak, M. L. Disis, J. R. Subjeck, and A. L. Kazim. Emergence of immune escape variant of mammary tumors that has distinct proteomic profile and a reduced ability to induce "danger signals." Breast Cancer Res Treat. In press.
3. Overwijk, W. W., M. R. Theoret, S. E. Finkelstein, D. R. Surman, L. A. de Jong, F. A. Vyth-Dreese, T. A. Dellemijn, P. A. Antony, P. J. Spiess, D. C. Palmer, et al 2003. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8⁺ T cells. J. Exp. Med. 198: 569-580. [Abstract/Free Full Text]

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