Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen–Specific T Cells
| Autor: | Paul Zolkind, Ravindra Uppaluri, Megan Morisada, Jay Friedman, Paul E. Clavijo, Wojciech K. Mydlarz, Clint T. Allen, Ellen C. Moore, James W. Hodge, Sarah Greene, Hans Schreiber, Lillian Sun, Nicole C. Schmitt, Carter Van Waes, Yvette Robbins |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Subdominant T-Lymphocytes medicine.medical_treatment Programmed Cell Death 1 Receptor Immunodominance Article Mice 03 medical and health sciences 0302 clinical medicine Antigen Cell Line Tumor Tumor Microenvironment Animals Humans Medicine Immunodominant Epitopes business.industry Antibodies Monoclonal Immunotherapy medicine.disease Xenograft Model Antitumor Assays Primary tumor Neoadjuvant Therapy Tumor antigen Immune checkpoint Blockade Mice Inbred C57BL 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Mouth Neoplasms business |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-19-2209 |
| Popis: | Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus–negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas. |
| Databáze: | OpenAIRE |
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