Boosting pre-existing, naturally occurring cytolytic CD8 + T-cell (CTLs) responses directed against class-I MHC-restricted peptides of tumor antigens, represents a primary goal of cancer immunotherapy. The number of pre-existing antitumor CTLs and their impaired function has been incriminated as the most likely candidates for the reduced clinical efficacy of these trials. This study was scheduled to determine possible differences in the frequency and the function of naturally occurring CTL precursors (pCTLs) against multiple peptides derived from the cancer-testis antigens MAGE-A1 and MAGE-A3, and the overexpressed antigen hTERT, in newly diagnosed lung cancer patients as compared with aged-matched healthy individuals. The cumulative frequency of circulating peptide-specific pCTLs was found significantly higher in the cancer patients, varied widely and was not affected by radiotherapy and chemotherapy. Furthermore, this frequency was greatly different between the various tumor-antigen peptides. Under the light of recent evidence provided from animal models, these results indicate that the peptide-specific pCTL frequency might represent an important determinant for the fate of cancer immunotherapy. In addition, our results show that tumorspecific pCTLs of cancer patients can present functional differences regarding their proliferative capacity, intensity of multimer staining and lytic capacity, when compared with those of healthy individuals. Hence, our findings could have an important role for the design of improved immunotherapeutic approaches for lung cancer. Keywords: HLA-multimers; peptide-specific CD8 + T-cells; tumor antigens; precursor frequency Boosting pre-existing, naturally occurring cytolytic CD8 + T-cell (CTL) responses directed against class-I major histocompatibility complex (MHC)-restricted peptides of tumor antigens, represents a primary goal of cancer immunotherapy. These CTLs, recognizing several tumor antigens, show in vitro a clear ability to lyse tumor cells expressing such molecules. However, the clinical effectiveness of active immunotherapy approaches using these antigens remains rather low, with tumor regressions appearing rarely and sporadically. 1 The underlying reasons of this ineffectiveness continue to be obscure, despite the great progress made over the last decade in understanding several aspects of the antitumor cytolytic T-cell response. The number of preexisting antitumor CTLs has been incriminated as one of the most likely candidates, although evidence toward this supposition was not convincing. Very recently, however, Rizzuto et al. 2 showed quite elegantly that the frequency of pre-existing tumor-antigen-specific CTL precursors (pCTL) in mice represents a critical determinant of the quality of the antitumor immune response, in accordance with the already recognized role that initial T-cell numbers have in the response against pathogens. 3,4
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