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.
Dr. Takemasa Tsuji joined the faculty in 2013 as an Assistant Professor of Oncology in the Center for Immunotherapy at Roswell Park Comprehensive Cancer Center. His research goal is to develop potent immunotherapeutic strategies that induce life-long tumor remission in broad cancer patients. He received bachelor’s and master’s degrees in Science from Hirosaki University and PhD from Hokkaido University in JAPAN. After obtaining his PhD, he conducted laboratory research as a post-doctoral research fellow in the laboratories of Dr. Takashi Nishimura (Hokkaido University), Dr. Lloyd J. Old (Ludwig Institute for Cancer Institute/Memorial Sloan-Kettering Cancer Center, NY), and Dr. Kunle Odunsi (Roswell Park Comprehensive Cancer Center, NY). His research during post-doctoral training has been focused on understanding the mechanisms of immunologic recognition of human cancers such that specific immunotherapies can be applied on a personalized basis.
His research in the past few years has led to the identification and characterization of a unique CD4+ T cell subset, which is named “tumor-recognizing CD4+ helper T cell (TR-CD4 cell)”, that directly recognizes cancer cells. Through direct recognition of cancer cells, TR-CD4 cells significantly inhibit tumor cell growth and potently induce or augment anti-tumor functions of other immune-cell subsets. To develop novel immunotherapy against ovarian cancers utilizing TR-CD4 cells, he will conduct preclinical research with the support from the Ovarian Cancer Research Alliance, Liz Tilberis Award. Dr. Tsuji received Alliance Foundation Awards from Roswell-Park Alliance foundation. He has also been a co-investigator in a New York State Stem Cell Science (NYSTEM) grant.