Function of T follicular helper cells in anti-tumor immunity

Abstract Clinical relapse and metastases are the major causes of death in melanoma. Currently, adoptive T cell therapy using tumor-infiltrating lymphocytes rich in cytotoxic CD8+ T cells (CTLs) is one of the promising approaches that helps overcome this major challenge in melanoma; however CTL cell transfer alone does not improve clinical response suggesting a role of helper CD4+ T cells. Recently, it has been noted that infiltration of a CD4+ T helper subset, named as T follicular helper (Tfh) cells into tumor sites correlates with increased survival of cancer patients; however their role in tumor immunity has not been clearly elucidated till date. In our hands, both pre-clinical murine tumor studies and patient studies show correlation between increased number of intratumoral Tfh cells and reduced melanoma tumor growth and improved survival, suggesting the novel function of Tfh cells in promoting anti-tumor immunity against melanoma. Remarkably, transfer of tumor antigen-specific Tfh cells in melanoma tumor-bearing mice results in increased intratumoral CTL number and function, as well as in more efficient tumor eradication, indicating the role of Tfh cells in antitumor immunity by promoting CTL expansion and/or activity. Moreover, we determined that Tfh derived cytokine interleukin (IL)-21 contributes to intratumoral CTL activity. Our results thus for first time indicate the therapeutic potential of Tfh cells in promoting anti-tumor immunity against melanoma and provide the basis for potential usage of these cells to improve current immunotherapy approaches.