ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration

Caihua Zhang, Kang Li, Hongzhang Zhu, Maosheng Cheng, Shuang Chen, Rongsong Ling, Cheng Wang and Demeng Chen ()
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Caihua Zhang: Sun Yat-sen University
Kang Li: Sun Yat-sen University
Hongzhang Zhu: Sun Yat-sen University
Maosheng Cheng: Sun Yat-sen University
Shuang Chen: Sun Yat-sen University
Rongsong Ling: Shenzhen University
Cheng Wang: Sun Yat-sen University
Demeng Chen: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers. Preclinical studies and mouse models suggest that therapies targeting CD276 may outperform PD1/PD-L1 blockade. However, data from mouse models indicate a significant non-responsive population to anti-CD276 treatment, with the mechanisms of resistance still unclear. In this study, we evaluate the activity of anti-CD276 antibodies in a chemically-induced murine model of head and neck squamous cell carcinoma. Using models of induced and orthotopic carcinogenesis, we identify ITGB6 as a key gene mediating differential responses to anti-CD276 treatment. Through single-cell RNA sequencing and gene-knockout mouse models, we find that ITGB6 regulates the expression of the tumor-associated chemokine CX3CL1, which recruits and activates PF4+ macrophages that express high levels of CX3CR1. Inhibition of the CX3CL1-CX3CR1 axis suppresses the infiltration and secretion of CXCL16 by PF4+ macrophages, thereby reinvigorating cytotoxic CXCR6+ CD8+ T cells and enhancing sensitivity to anti-CD276 treatment. Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-024-51096-0

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