A Rediscovered Immunomodulatory Action of Cancer Chemotherapy to Pilot the Cytokine Network in an Antitumor Way

Abstract

The recent proposal of cancer immunotherapy with anti-checkpoint inhibitor monoclonal antibodies, as well as the previous immunotherapy with IL-2, would require an interpretation of cancer chemotherapy not only in terms of therapeutic strategy carried out to destroy cancer cells, but also as an approach potentially able to influence and modulate the cytokine network in an attempt to correct cancer-related cytokine alterations responsible for tumor progression itself. This statement is justified by the fact that the efficacy of cancer immunotherapy is depending at least in part on the cytokine secretions of patients. Despite the great number of cancer-related cytokine alterations, the main alterations provided by a physiopathological and prognostic significance would consisting of low blood levels of IL-2 and IL-12 in association with abnormally high concentrations of IL-1, IL-6, TNF-alpha, IL-10 and TGF-beta. The effects of chemotherapy on cytokine secretions have appeared to depend on the type of agent, as well as on its dosage and schedule of administrarion. At present, the main effects of chemotherapy provided by a potential clinical application would be represented by the stimulatory action of adriamycin on IL-2 secretion, the inhibitory effect of cisplatin on IL-6 secretion, the stimulatory effect of gemcitabine on IL-12 production, and the inhibitory action of both cyclophosphamide and gemcitabine on regulatory T cell system. Then, the future chemo-immunotherapeuticregimenswouldhavenot to be elaborated not only on the bases of empiristic criteria and on the cytotoxic effects of che various chemotherapeutic agents, but also by taking into consideration their specific activity on the secretion of those cytokines, whose anomalous production has to be corrected and neutralized.