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Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells
Jay Friedman1, Ellen C Moore1, Paul Zolkind2
1Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
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.
Insights
Neoadjuvant programmed death receptor 1 (PD-1) blockade before surgery can overcome tumor immune evasion in head and neck cancer. This approach enhances T-cell responses and establishes protective immunologic memory against tumor recurrence.
Area of Science:
- Oncology
- Immunology
- Head and Neck Cancer Research
Background:
- Surgical resection with lymphadenectomy is standard for advanced human papillomavirus-negative head and neck squamous cell carcinoma.
- High rates of locoregional and distant relapse persist despite achieving clear surgical margins.
- Clinical data supporting perioperative immunotherapy, including neoadjuvant or adjuvant treatment, are limited.
Purpose of the Study:
- To investigate the mechanistic effects of programmed death receptor 1 (PD-1) blockade in the context of surgical resection for oral cavity carcinoma.
- To explore how PD-1 blockade influences T-cell responses against multiple tumor antigens.
Main Methods:
- Utilized two syngeneic oral cavity carcinoma models.
- Administered PD-1 monoclonal antibody (mAb) before or after primary tumor resection.
- Assessed antigen-specific T-cell responses using functional and in vivo challenge assays.
Main Results:
- Observed functional immunodominance among T cells targeting multiple tumor antigens, with PD-1 expression higher on T cells specific for subdominant antigens.
- Neoadjuvant PD-1 blockade, but not adjuvant, disrupted immunodominance, eliciting responses to both dominant and subdominant antigens.
- In a model of antigen escape, neoadjuvant PD-1 blockade induced effector T-cell immunity against tumors lacking the dominant antigen but retaining subdominant antigens.
- Combined neoadjuvant PD-1 blockade with surgery generated immunologic memory preventing subsequent tumor engraftment.
Conclusions:
- PD-1 expression on T cells contributes to functional immunodominance within progressing tumors.
- Neoadjuvant PD-1 blockade shows promise for overcoming immune evasion in surgically resectable carcinomas.
- These findings support the clinical investigation of neoadjuvant PD-1 blockade in patients with head and neck cancer.
