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Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma

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Abstract

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs’ inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.

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Abbreviations

aCTLA4:

Anti-CTLA4

CTLA4:

Cytotoxic T-lymphocyte-associated antigen 4

Dys:

Dysplasia

HNSCC:

Head and neck squamous cell carcinoma

HPV:

Human papillomavirus

LN:

Lymph node

MDSCs:

Myeloid-derived suppressor cells

SFKs:

Src family kinases

TAMs:

Tumor-associated macrophages

TIL:

Tumor infiltrate lymphocytes

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Acknowledgements

We thank Zhi-Yong Chen and Dong Chen for excellent technical support. And also thank Wuhan Institute of Biotechnology for their Public Technology Service Platform. Meanwhile, this study was supported by National Natural Science Foundation of China (NFSC): 81672668, 81472528, and 81472529, and the Fundamental Research Funds for the Central Universities (2042017kf0171).

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Author notes

  1. Guang-Tao Yu and Liang Mao contributed equally.

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, China

    Guang-Tao Yu, Liang Mao, Lei Wu, Wei-Wei Deng, Lin-Lin Bu, Jian-Feng Liu, Lei Chen, Lei-Lei Yang, Hao Wu, Wen-Feng Zhang & Zhi-Jun Sun

  2. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China

    Lin-Lin Bu, Wen-Feng Zhang & Zhi-Jun Sun

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  1. Guang-Tao Yu
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Correspondence to Wen-Feng Zhang or Zhi-Jun Sun.

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Animal studies were approved and supervised by the Animal Care and Use Committee of Wuhan University. The ethical approval number is 2014C66.

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The authors declare that they have no competing interests.

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Yu, GT., Mao, L., Wu, L. et al. Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma. Cell. Mol. Life Sci. 75, 4223–4234 (2018). https://doi.org/10.1007/s00018-018-2863-3

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  • DOI: https://doi.org/10.1007/s00018-018-2863-3

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