Abstract
Characterization of tumor antigen-specific CD4 T-cell responses in healthy donors and malignant melanoma patients using an in vitro amplified T-cell library screening procedure. A high-throughput, human leukocyte antigen (HLA)-independent approach was used to estimate at unprecedented high sensitivity level precursor frequencies of tumor antigen- and neoantigen-specific CD4 T cells in healthy donors and patients with cancer. Frequency estimation was combined with isolation and functional characterization of identified tumor-reactive CD4 T-cell clones. In healthy donors, we report frequencies of naïve tumor-associated antigen (TAA)-specific CD4 T cells comparable with those of CD4 T cells specific for infectious agents (Tetanus toxoid). Interestingly, we also identified low, but consistent numbers of memory CD4 T cells specific for several TAAs. In patients with melanoma, low frequencies of circulating TAA-specific CD4 T cells were detected that increased after peptide-based immunotherapy. Such antitumor TAA-specific CD4 T-cell responses were also detectable within the tumor-infiltrated tissues. TAA-specific CD4 T cells in patients displayed a highly polyfunctional state, with partial skewing to Type-2 polarization. Finally, we report the applicability of this approach to the detection and amplification of neoantigen-specific CD4 T cells. This simple, noninvasive, high-throughput screening of tumor- and neoantigen-specific CD4 T cells requires little biologic material, is HLA class II independent and allows the concomitant screening for a large number of tumor antigens of interest, including neoantigens. This approach will facilitate the immunomonitoring of preexisting and therapy-induced CD4 T-cell responses, and accelerate the development of CD4 T-cell-based therapies.
Highlights
The realization that human tumors express T-cell–defined tumor associated antigens (TAA) has been the cornerstone to develop T-cell–based cancer immunotherapies
Note: Supplementary data for this article are available at Clinical Cancer Research Online
Tumor infiltration by Th1-polarized CD4 T cells has been associated with better survival in patients with different types of tumors, while the presence of cells with Th2 and Treg phenotypes most often correlates with poor prognosis [6]
Summary
The realization that human tumors express T-cell–defined tumor associated antigens (TAA) has been the cornerstone to develop T-cell–based cancer immunotherapies In this context, strategies comprising cancer vaccines, adoptive T-cell transfer therapies, and mAbs have been tested in the clinical setting aiming to improve antitumor T-cell responses [1]. Strategies comprising cancer vaccines, adoptive T-cell transfer therapies, and mAbs have been tested in the clinical setting aiming to improve antitumor T-cell responses [1] Some of these approaches have recently led to impressive clinical responses, resulting in a rapidly increasing number of immunotherapy agents approved by the FDA and European Medicines Agency for the treatment of different types of solid tumors and hematologic malignancies [2,3,4]. Recent observations show that CD4 T cells are exquisitely sensitive to sensing and recognition of "neoepitopes," a category of antigens that hold great promise in cancer immunotherapy [8,9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Clinical cancer research : an official journal of the American Association for Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
