Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen–specific T cells

Jay Friedman, Ellen C. Moore, Paul Zolkind, Yvette Robbins, Paul E. Clavijo, Lilian Sun, Sarah Greene, Megan V. Morisada, Wojciech K. Mydlarz, Nicole Schmitt, James W. Hodge, Hans Schreiber, Carter van Waes, Ravindra Uppaluri, Clint Allen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)679-689
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number3
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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