Targeting cancer-associated fibroblasts to enhance immunotherapy in head and neck cancers

Abstract

Despite significant advances in immunotherapy, response rates in head and neck squamous cell carcinoma (HNSCC) remain critically low, with only ~15% of patients benefiting from current treatments such as anti-PD-1 inhibitors. This limited efficacy is primarily attributed to the immunosuppressive tumour microenvironment, particularly the abundance of myofibroblastic cancer-associated fibroblasts (myCAFs), which hinder immune infiltration and protect tumour cells from immune-mediated destruction. Strategies to deplete or reprogram myCAFs could significantly improve immunotherapy responses; however, the lack of specific myCAF markers has posed a major challenge.

This study identified MAGED4B, a cancer/testis antigen, as a promising dual marker of tumour cells and myCAFs in HNSCC. Single-cell RNA sequencing revealed selective MAGED4B expression in myCAF and malignant populations, with minimal expression in other stromal or immune cells. Immunohistochemistry analysis of 53 HNSCC patient samples validated this finding, with MAGED4B expression detected in tumour cells (43/53) and myCAFs (25/53). These findings support MAGED4B as a novel target for therapeutic intervention in myCAF-rich HNSCC.

To explore its therapeutic potential, a murine oral cancer model was developed to mimic myCAF-rich tumours. A pDOM DNA fusion vaccine targeting MAGED4B elicited a robust CD8+ T cell response in vivo, as demonstrated by IFNγ ELISpot assays. In the absence of myCAFs, MAGED4B-targeted vaccination significantly reduced tumour growth (p=0.0414) and improved survival (p=0.0389), demonstrating the vaccine’s potential efficacy. However, the presence of myCAFs compromised vaccine efficacy, highlighting the immunosuppressive role of myCAFs within the tumour microenvironment.

To identify additional therapeutic targets for disrupting myCAF activity, a CRISPR/Cas9 screen was employed using TGF-β1-treated fibroblasts to identify regulators of the myCAF phenotype. Over 100 candidate genes were identified, including those implicated in the regulation of αSMA expression, with ongoing investigations prioritising the most promising hits for therapeutic targeting.

These findings suggest that MAGED4B-directed immunotherapy represents a dual-target strategy to overcome immunotherapy resistance by targeting both tumour cells and stromal barriers. HNSCC, characterised by extensive desmoplasia and frequent myCAF enrichment, poses a significant clinical challenge, particularly in patients resistant to conventional immunotherapy. The combination of MAGED4B-targeted vaccination with other immunotherapeutic approaches, such as immune checkpoint inhibitors, holds potential to enhance immune infiltration, disrupt stromal defences, and improve outcomes in therapy-resistant HNSCC.

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Identifiers

ORCID for Josephine Frances Buckingham: orcid.org/0000-0002-6314-973X

ORCID for Chris Hanley: orcid.org/0000-0003-3816-7220

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