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DNA-double strand breaks enhance the expression of major histocompatibility complex class II through the ATM-NF-κΒ-IRF1-CIITA pathway

Cancer Gene Therapy volume 29, pages 225–240 (2022)Cite this article

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Abstract

Major histocompatibility complex class II (MHC II) is important for the adaptive immune response because MHC II presents processed antigens to a cluster of differentiation 4 (CD4)-positive T-cells. Conventional doses of chemotherapeutic agents induce tumor cell death by causing DNA double-strand breaks (DSBs). However, cellular responses caused by sub-lethal doses of chemotherapeutic agents are poorly understood. In this study, using low doses of chemotherapeutic agents, we showed that DSBs enhanced the expression of MHC II on cells that originate from antigen-presenting cells (APCs). These agents induced the MHC class II transactivator (CIITA), the master regulator of MHC II, and interferon regulatory factor 1 (IRF1), a transcription factor for CIITA. Short hairpin RNA against IRF1 suppressed chemotherapeutic agent-induced CIITA expression, whereas exogenous expression of IRF1 induced CIITA. Inhibition of ataxia-telangiectasia mutated (ATM), a DSB-activated kinase, suppressed induction of IRF1, CIITA, and MHC II. Similar results were observed by inhibiting NF-κB, a downstream target of ATM. These results suggest that DSBs induce MHC II activity via the ATM-NF-κB-IRF1–CIITA pathway in cells that intrinsically present antigens. Additionally, chemotherapeutic agents induced T-cell regulatory molecules. Our findings suggest that chemotherapeutic agents enhance the antigen presentation activity of APCs for T-cell activation.

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Fig. 1: Chemotherapeutic agents enhance MHC II expression in cells originating from APCs.
Fig. 2: MEL induces the expression of CIITA and IRF1 in MM cells.
Fig. 3: ATM is required for MEL-induced expression of MHC II, CIITA, and IRF1.
Fig. 4: NF-κB is required for MEL-induced expression of MHC II, CIITA, and IRF1.
Fig. 5: Overexpression of c-MYC induces DSBs and the expression of IRF1, CIITA, and MHC II.
Fig. 6: MEL induces CD86, CD137L, PD1, and CD70.
Fig. 7: A hypothetical model of DSBs-activated tumor immunity through MHC II expression.

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Data availability

Microarray data from this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database. The GEO accession number is GSE151040.

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Acknowledgements

We thank K. Tomizawa for technical help and H. Miyoshi, T. Otsuki, M. Ri, and H. Tamura for generous gifts of materials. We also thank the Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, The Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan

    Tsukasa Oda & Takayuki Yamashita

  2. Center for Food Science and Wellness, Gunma University, Maebashi, Gunma, Japan

    Tsukasa Oda

  3. Graduate School of Health Sciences, Gunma University, Maebashi, Gunma, Japan

    Ruri Nakamura, Tetsuhiro Kasamatsu, Nanami Gotoh, Takayuki Saitoh & Hirokazu Murakami

  4. Department of Molecular Diagnostics and Therapeutics, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan

    Keiko Okuda

  5. Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan

    Hiroshi Handa

  6. Gunma University of Health and Welfare, Maebashi, Gunma, Japan

    Hirokazu Murakami

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Oda, T., Nakamura, R., Kasamatsu, T. et al. DNA-double strand breaks enhance the expression of major histocompatibility complex class II through the ATM-NF-κΒ-IRF1-CIITA pathway. Cancer Gene Ther 29, 225–240 (2022). https://doi.org/10.1038/s41417-021-00302-y

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