Targeting Dendritic Cell Dysfunction to Circumvent Anti-PD1 Resistance in Head and Neck Cancer
Shin Saito1, Michihisa Kono1, Hoang C B Nguyen2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
Neoadjuvant anti-PD1 (aPD1) therapies are being explored in surgically resectable head and neck squamous cell carcinoma (HNSCC). Encouraging responses have been observed, but further insights into the mechanisms underlying resistance and approaches to improve responses are needed.
Experimental Design:
We integrated data from syngeneic mouse oral carcinoma (MOC) models and neoadjuvant pembrolizumab HNSCC patient tumor RNA-sequencing data to explore the mechanism of aPD1 resistance. Tumors and tumor-draining lymph nodes (DLN) from MOC models were analyzed for antigen-specific priming. CCL5 expression was enforced in an aPD1-resistant model.
Results:
An aPD1-resistant mouse model showed poor priming in the tumor DLN due to type 1 conventional dendritic cell (cDC1) dysfunction, which correlated with exhausted and poorly responsive antigen-specific T cells. Tumor microenvironment analysis also showed decreased cDC1 in aPD1-resistant tumors compared with sensitive tumors. Following neoadjuvant aPD1 therapy, pathologic responses in patients also positively correlated with baseline transcriptomic cDC1 signatures. In an aPD1-resistant model, intratumoral cDC1 vaccine was sufficient to restore aPD1 response by enhancing T-cell infiltration and increasing antigen-specific responses with improved tumor control. Mechanistically, CCL5 expression significantly correlated with neoadjuvant aPD1 response and enforced expression of CCL5 in an aPD1-resistant model, enhanced cDC1 tumor infiltration, restored antigen-specific responses, and recovered sensitivity to aPD1 treatment.
Conclusions:
These data highlight the contribution of tumor-infiltrating cDC1 in HNSCC aPD1 response and approaches to enhance cDC1 infiltration and function that may circumvent aPD1 resistance in patients with HNSCC.
Insights
Type 1 conventional dendritic cell (cDC1) dysfunction contributes to anti-PD1 (aPD1) resistance in head and neck squamous cell carcinoma (HNSCC). Enhancing cDC1 infiltration and function, potentially via CCL5, can restore aPD1 sensitivity and improve tumor control.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Neoadjuvant anti-PD1 (aPD1) therapies show promise in head and neck squamous cell carcinoma (HNSCC).
- Mechanisms of resistance to aPD1 therapy require further investigation to improve patient outcomes.
- Understanding immune cell roles in HNSCC treatment response is crucial.
Purpose of the Study:
- To investigate the mechanisms of aPD1 resistance in HNSCC.
- To identify immune cell populations critical for aPD1 response in HNSCC.
- To explore strategies for overcoming aPD1 resistance in HNSCC.
Main Methods:
- Integrated analysis of syngeneic mouse oral carcinoma (MOC) models and HNSCC patient RNA-sequencing data.
- Assessment of antigen-specific T-cell priming in tumor-draining lymph nodes (DLN).
- Evaluation of type 1 conventional dendritic cell (cDC1) function and tumor microenvironment in aPD1-resistant models.
Main Results:
- aPD1 resistance in mouse models was linked to cDC1 dysfunction and impaired T-cell responses.
- Reduced cDC1 infiltration correlated with aPD1 resistance in both mouse models and HNSCC patients.
- Intratumoral cDC1 vaccination and CCL5 expression restored aPD1 sensitivity by enhancing T-cell infiltration and responses.
Conclusions:
- Tumor-infiltrating cDC1 play a critical role in HNSCC response to aPD1 therapy.
- Strategies to enhance cDC1 infiltration and function may overcome aPD1 resistance in HNSCC.
- CCL5 emerges as a potential therapeutic target to improve aPD1 efficacy in HNSCC.
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