The potential of tumor-specific Th2 cells for cancer immunotherapy by adoptive transfer

Immunotherapy based on adoptive cell transfer (ACT) of tumor-specific T cells, either naturally occurring or gene engineered, represents a promising strategy to cure cancer. To date the majority of ACT trials have focused on cytotoxic CD8+ T cells, which cave the ability to recognize and kill cancer cells directly. The potential of CD4+ T helper cells has in the recent years been increasingly appreciated. There are several subsets of CD4+ T cells, including Th1, Th2, Th17, and regulatory T cells, which differ greatly in terms of cytokine secretion and effector functions. It is not known which subset can provide the greatest efficacy for ACT. Here, we have investigated the efficacy of in vitro expanded, tumor-specific Th2 cells for the treatment of mice with MHC class II negative myeloma. The transferred Th2 cells were confirmed to have a true Th2 phenotype, producing the Th2-prototype cytokines IL-4, IL- and IL-13. The Th2 cells could very efficiently provide tumor cell eradication after intravenous transfer into immunodeficient mice challenged with subcutaneous myeloma inoculation. The Th2-accosiated cytokines IL-4 and IL-13 are known to induce alternative activation of macrophages into an M2 phenotype. M2 macrophages produce the enzyme arginase-1 and the potential of this enzyme being an effector molecule, was investigated. Blocking experiments revealed arginase-1 was required for efficient cancer eradication. These results show that there might be a great potential for Th2 cells in ACT, and that the Th2 cells possibly cause cancer eradication through the differentiation of macrophages into an arginase-1-producing M2 phenotype.