Tumor antigen-specific CD4+ T cells in cancer immunity: from antigen identification to tumor prognosis and development of therapeutic strategies

CD4+ T cells comprise a large fraction of tumor infiltrating lymphocytes and it is now established that they may exert an important role in tumor immune‐surveillance. Several CD4+ T cell subsets [i.e. T helper (Th)1, Th2, T regulatory (Treg), Th17, Th22 and follicular T helper (Tfh)] have been described and differentiation of each subset depends on both the antigen presenting cells responsible for its activation and the cytokine environment present at the site of priming. Tumor antigen‐specific CD4+ T cells with different functional activity have been found in the blood of cancer patients and different CD4+ T cell subsets have been identified at the tumor site by the expression of specific transcription factors and the profile of secreted cytokines. Importantly, depending on the subset, CD4+ T cells may exert antitumor versus pro‐tumor functions. Here we review the studies that first identified the presence of tumor‐specific CD4+ T cells in cancer patients, the techniques used to identify the tumor antigens recognized, the role of the different CD4+ T cell subsets in tumor immunity and in cancer prognosis and the development of therapeutic strategies aimed at activating efficient antitumor CD4+ T cell effectors.