Cancer is the number one cause of death worldwide and approximately 75% of skin cancer deaths are from melanoma. To date, adoptive T cell therapy is a promising approach to reactivate the patient’s own immune system to fight against tumors. While adoptive transfer of tumor-infiltrating lymphocytes enriched with cytotoxic CD8+ T cells (CTLs) have resulted in a 50% response rate in multiple phase II clinical trials in metastatic melanoma, CTL transfer alone does not improve clinical response suggesting an essential role of helper CD4+ T cells. There is increasing evidence on the potential function of a CD4+ T helper subset, named as T follicular helper (Tfh) cells in triggering anti-tumor acti...

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Cancer is the number one cause of death worldwide and approximately 75% of skin cancer deaths are from melanoma. To date, adoptive T cell therapy is a promising approach to reactivate the patient’s own immune system to fight against tumors. While adoptive transfer of tumor-infiltrating lymphocytes enriched with cytotoxic CD8+ T cells (CTLs) have resulted in a 50% response rate in multiple phase II clinical trials in metastatic melanoma, CTL transfer alone does not improve clinical response suggesting an essential role of helper CD4+ T cells. There is increasing evidence on the potential function of a CD4+ T helper subset, named as T follicular helper (Tfh) cells in triggering anti-tumor activity; however, the role of Tfh cells in tumor immunity has not been elucidated. Our preliminary mouse studies suggest that intratumoral Tfh cells are one of the key players in melanoma regression. In support of our mouse studies, the presence of intratumoral Tfh cells in stage III melanoma patients correlates with their improved overall survival. Remarkably, adoptive transfer of Tfh cells in melanoma tumor-bearing mice results in increase in intratumoral CTL number, as well as in more efficient tumor eradication, further indicating the potential role of Tfh cells in antitumor immunity by promoting CTL expansion and/or activity. Based on these data, we hypothesize that Tfh cells are important mediators of anti-tumor responses and Tfh-based immunotherapy approach might aid to improve the efficacy of the immune system against malignancies. Therefore, by utilizing both mouse and melanoma patient Tfh cells, we propose to validate their therapeutic potential for melanoma treatment and identify regulatory mechanisms whereby Tfh cells contribute to anti-tumor immunity. Upon successful completion, we will be able to better understand the functions of Tfh cells within melanoma as well as establish safe and efficient Tfh-based immunotherapy strategy for treatment of established tumors.

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