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Abstract
Combination of chemotherapy and immunotherapy to increase the effectiveness of an antitumor immune response is currently regarded as an attractive antitumor strategy. In a pilot clinical trial, we have recently documented an increase of melanoma antigen A (Melan-A)-specific, tumor-reactive, long-lasting effector-memory CD8(+) T cells after the administration of dacarbazine (DTIC) 1 day before peptide vaccination in melanoma patients. Global transcriptional analysis revealed a DTIC-induced activation of genes involved in the immune response and leukocyte activation. To identify the possible mechanisms underlying this improved immune response, we have compared the endogenous and the treatment-induced anti-Melan-A response at the clonal level in patients treated with the vaccine alone or with DTIC plus vaccine. We report a progressive widening of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, only in Melan-A-specific T-cell clones of patients treated with chemoimmunotherapy, with a trend toward longer survival. Differently, patients treated with vaccine alone showed a tendency to narrowing the TCR repertoire diversity, accompanied by a decrease of tumor lytic activity in one patient. Collectively, our findings indicate that DTIC plus vaccination shapes the TCR repertoire in terms of diversity and antitumor response, suggesting that this combined therapy could be effective in preventing melanoma relapse.
Highlights
Accumulating evidence indicates that the immune system is capable of recognizing tumor antigens and counteracting tumor progression, rendering cancer vaccines an attractive clinical approach for cancer patients [1]
We have recently reported the results of a pilot clinical trial showing that, in HLA-A*0201 (HLA-A2 hereafter) disease-free melanoma patients receiving dacarbazine (DTIC) 1 day before melanoma antigen A (Melan-A) and gp100 peptide vaccination, a long-lasting tumor-reactive memory Melan-A–specific CD8+ T-cell response is induced, concomitant with a DTIC-driven activation of genes involved in immune response, cell motility, cytokine production [i.e., interleukin-15 (IL-15)], and leukocyte activation [11]
The results show that a progressive enhancement of T-cell receptor (TCR) repertoire diversity, accompanied by high avidity and tumor reactivity, occurs only in patients treated with the combined DTIC vaccine therapy
Summary
Accumulating evidence indicates that the immune system is capable of recognizing tumor antigens and counteracting tumor progression, rendering cancer vaccines an attractive clinical approach for cancer patients [1]. Many efforts in developing therapeutic vaccines have been pursued over the years [2,3,4], but clinical efficacy has rarely been observed [5]. These trials have gathered a wealth of biological information about mechanisms of immune recognition involving a dynamic interplay between cancer cells, tumor. Authors' Affiliations: 1Laboratory of Immunology, Department of Experimental Oncology and 2Department of Medical Oncology, Regina Elena National Cancer Institute; 3Melanoma Unit, Department of Dermatology-Oncology, S. Gallicano Dermatological Institute; 4Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy and 5Laboratory of Biotechnology, Diagnostic Department, Spedali Civili di Brescia, Brescia, Italy.
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