Dataset Information

PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance.

ABSTRACT:

Background

Tumor models resistant to EGFR tyrosine kinase inhibitors or cisplatin express higher levels of the immune checkpoint molecule PD-L1. We sought to determine whether PD-L1 expression is elevated in head and neck squamous cell carcinoma (HNSCC) models of acquired cetuximab resistance and whether the expression is regulated by bromodomain and extraterminal domain (BET) proteins.

Methods

Expression of PD-L1 was assessed in HNSCC cell line models of acquired cetuximab resistance. Proteolysis targeting chimera (PROTAC)- and RNAi-mediated targeting were used to assess the role of BET proteins.

Results

Cetuximab-resistant HNSCC cells expressed elevated PD-L1 compared to cetuximab-sensitive controls. Treatment with the BET inhibitor JQ1, the BET PROTAC MZ1, or RNAi-mediated knockdown of BRD2 decreased PD-L1 expression. Knockdown of BRD2 also reduced the elevated levels of PD-L1 seen in a model of acquired cisplatin resistance.

Conclusions

PD-L1 is significantly elevated in HNSCC models of acquired cetuximab and cisplatin resistance where BRD2 is the primary regulator.

SUBMITTER: Bhola NE

PROVIDER: S-EPMC8664160 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance.

Bhola Neil E NE Njatcha Christian C Hu Lanlin L Lee Eliot D ED Shiah Jamie V JV Kim Mi-Ok MO Johnson Daniel E DE Grandis Jennifer R JR

Head & neck 20210803 11

<h4>Background</h4>Tumor models resistant to EGFR tyrosine kinase inhibitors or cisplatin express higher levels of the immune checkpoint molecule PD-L1. We sought to determine whether PD-L1 expression is elevated in head and neck squamous cell carcinoma (HNSCC) models of acquired cetuximab resistance and whether the expression is regulated by bromodomain and extraterminal domain (BET) proteins.<h4>Methods</h4>Expression of PD-L1 was assessed in HNSCC cell line models of acquired cetuximab resist ...[more]

PMID: 34346116

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Project description:BackgroundThe PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking.Patients and methodsWe assessed PD-L1 and PD-L2 expression via immunohistochemistry in two independent cohorts of 293 HNSCC patients.ResultsA significant subset of HNSCC showed high expression levels of PD-L1. Most remarkable, we detected a strong correlation between PD-L1 expression and overall survival time in both HNSCC cohorts. Further, in multivariate cox proportional hazard models, PD-L1 dominates as the strongest prognostic factor of patient's outcome in HNSCC, leaving even tumor stage and distant metastasis behind. Moreover, strong PD-L1 expression was associated with the presence of distant metastases in a subset of cases.ConclusionsIn summary, while the significance of PD-L2 in HNSCC seems to minor, we show that PD-L1 expression is common in HNSCC and, more importantly, a both robust and strong prognostic biomarker. In this respect, our results provide hints on further application of therapies targeting the PD-1/PD-L1 pathway in HNSCC. Investigation of response and outcome of patients receiving anti-PD-1/PD-L1 containing therapies in correlation with PD-L1 expression analysis should be an important task for the future.Statement of translational relevanceIn spite of improved treatment options and increasing knowledge of molecular alterations in HNSCC, the survival rate has not been dramatically changed in the past decades. Pies are missing in HNSCC. One promising candidate in cancer immune therapy is PD-L1. Drugs targeting PD-L1 or its receptor PD-1 are subject of several clinical studies in different cancer entities. However, comprehensive data about PD-L1 expression in HNSCC and therefore a rational basis for anti PD-L1/PD-1 therapy in HNSCC is lacking. Here, we provide wide-ranging data about PD-L1 expression in HNSCC of all major localizations. We observed a strong correlation between expression of PD-L1 and reduced overall survival time. Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient's outcome when verified together with recognized prognostic factors.

Project description:IntroductionImmune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study's main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings.Materials and methodsThis is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies.ResultsWe analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65-0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity.Discussion and conclusionsOur data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

Project description:Introduction and backgroundHead and neck squamous cell carcinoma (HNSCC) has been increasingly recognized as an immune suppressive malignancy. The efficacy of immune checkpoint inhibitors (ICI's) in the context of recurrent/metastatic (R/M) setting anticipates the possible integration of immunotherapy into the therapeutic armamentarium of locally advanced disease. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising data in R/M HNSCC. The aim of our study is to test the antitumor activity of a combined regimen incorporating an immune checkpoint inhibitor into a conventional bio-radiation strategy for the cure of unfavorable locally advanced HNSCC.Methods/designIn this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive Radiotherapy (RT) (69.9 Gy/2.12 Gy in 33 fractions) with concurrent Cetuximab (CTX) (400 mg/m2 1 week before RT start followed by 250 mg/m2 weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years) will be eligible.DiscussionConventional intensification strategies failed to provide any benefit for the cure of locally advanced HNSCC. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, ultimately aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active.Trial registrationNCT number: NCT03051906Eudract number: 2016-004668-20.

Dataset Information

PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance.

Background

Methods

Results

Conclusions

Publications

PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance.

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