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Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

ABSTRACT: Immune checkpoint blockers (ICBs) targeting programmed death 1(PD-1) are considered effective first-line therapy against PD-1 ligand (PD-L1)-expressing head and neck squamous cell carcinoma (HNSCC). However, associated changes in tumor microenvironment (TME) and mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa. Single-cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou Oral Cancer (AOC) cell lines. Subsequently, a syngeneic PD-L1-expressing HNSCC xenograft model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD-L1 expression. ICB monotherapy induced global changes in TME, including vascular normalization. Furthermore, the anti-tumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and anti-vascular endothelial growth factor receptor 2 inhibitors. The ICB-induced anti-tumorigenicity and TME normalization were alleviated by blocking the Type I interferon pathway.In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the Type-I interferon pathway is indispensable in realizing ICB effects. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against HNSCC expressing PD-L1 in the KEYNOTE-048 trial. This model can assist future research on HNSCC immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE248271 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

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Immune checkpoint inhibitor monotherapy is sufficient to promote microenvironmental normalization via Type I interferon pathway in PD-L1+ expressing head and neck cancer

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