Tumor antigen-specific CD4+ T cells play a central role in orchestrating adaptive and innate immune cells by provision of “CD4-help” for efficient immune surveillance against malignancy. Functional antigen-presenting cells (APCs) are indispensable for activation of antigen-specific CD4+ T cells. However, APCs in the tumor microenvironment are frequently dysfunctional, resulting in limitation of CD4+ T-cell function. Lack of “CD4-help” can explain rapid exhaustion of immune cells in the tumor microenvironment. We recently identified and characterized a unique human CD4+ T-cell population in ovarian cancer patients which directly recognizes cancer cells in MHC class II-restricted and antigen-specific manner. This tumor-recognizing CD4+ T (TR-CD4) cells could overcome immunosuppression in the tumor microenvironment by efficient provision of “CD4-help” without the need of functional APCs. Indeed TR-CD4 cells directly inhibited in vitro and in vivo tumor growth for melanoma mouse model. In addition, TR-CD4 cells enhanced effector and memory functions of the cognate tumor antigen-specific CD8+ T cells in the absence of APCs. These observations led to the development of immunotherapeutic strategy harnessing tumor-recognizing CD4+ T cells, which could dramatically improve current adoptive T cell therapy (ACT) using MHC class I-restricted T cell receptor (TCR) engineering cells. Our central hypothesis is that TR-CD4 cells play a key role in anti-tumor immunity by revitalizing tumor-specific CD8+ T cells to kill cancer cells, which would be associated with clinical outcome of patients with ovarian cancer and induce complete tumor regression by ACT harnessing TR-CD4 cells.
Based on our hypothesis, we propose three aims: (i) To characterize TR-CD4 cells in ovarian cancer patients; (ii) To establish a method for generating TR-CD4 cells by TCR gene-engineering; and (iii) To optimize a therapeutic protocol for TR-CD4 ACT in human ovarian cancer xenograft models. This project will be the first study to examine the role of tumor-recognizing CD4+ T cells in cancer patients. The observations would be obtained from the project will provide a new insight in the role and function of a unique population of CD4+ T cells (TR-CD4 cells) in ovarian cancer patients. Furthermore, the development of the strategy utilizing TR-CD4 cells by gene-engineering will have broad applicability for cancer patients in clinical trials.