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Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer

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Abstract

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8+ TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8+ TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8+ TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8+ TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8+ TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8+ TILs and immune-active TME.

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Data availability

The datasets generated during and/or analyzed during the current study are available from corresponding author on reasonable request.

Abbreviations

CCL5:

C–C chemokine ligand-5

cGAMP:

Cyclic GMP-AMP

cGAS:

Cyclic GMP-AMP synthase,

CIN:

Chromosomal instability

CRC:

Colorectal cancer

CXCL10:

C-X-C motif ligand 10

dMMR:

Mismatch repair deficient

ICI:

Immune checkpoint inhibitor

IRF3:

Interferon regulatory factor 3

MLH1:

MutL homolog 1

MSH2:

MutS homolog 2

MSH6:

MutS homolog 6

MSI:

Microsatellite instability

MSS:

Microsatellite stable

pMMR:

Mismatch repair proficient

PMS2:

PMS1 homolog 2

STING:

Stimulator of interferon genes

TREX1:

Three-prime repair exonuclease 1

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Acknowledgements

This work was supported by the grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to S. Nakajima and K. Kono). We thank Masayo Sugeno, Sakino Arai, Eri Takahashi, and Saori Naruse for excellent technical assistant and helpful secretarial assistance.

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Authors and Affiliations

  1. Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima city, Fukushima, 960-1295, Japan

    Akinao Kaneta, Shotaro Nakajima, Hirokazu Okayama, Takuro Matsumoto, Katsuharu Saito, Tomohiro Kikuchi, Eisei Endo, Misato Ito, Kosaku Mimura, Yasuyuki Kanke, Motonobu Saito, Zenichiro Saze, Shotaro Fujita, Wataru Sakamoto, Hisashi Onozawa, Tomoyuki Momma, Shinji Ohki & Koji Kono

  2. Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan

    Kosaku Mimura

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  1. Akinao Kaneta
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  2. Shotaro Nakajima
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  3. Hirokazu Okayama
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  4. Takuro Matsumoto
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Contributions

SN and KK contributed to the study conception. SN, HO, KM, and KK contributed to the supervision of the study. Material preparation was performed by AK, SN, and KS. Data curation and analysis were performed by SN, AK, and HO. Data collection and investigation were performed by AK, SN, TMa, KS, TK, EE. Patient recruitment was carried out by AK, HO, TMa, TK, EE, MI, YK, MS, ZS, SF, WS, HO, TMo, and SO. The first draft and the revised version of the manuscript were written by AK, SN, and KK. All authors read and approved the manuscript.

Corresponding author

Correspondence to Shotaro Nakajima.

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No potential conflicts of interest relevant to this article were reported.

Ethics approval

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Fukushima Medical University (Fukushima, Japan). Cell line authentication: Human colorectal cancer cell lines were purchased from the Korean Cell Line Bank (SNU81) and the American Type Culture Collection (SW480), and the cell lines have been authenticated using STR analysis (Promega Japan, Tokyo, Japan).

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Kaneta, A., Nakajima, S., Okayama, H. et al. Role of the cGAS-STING pathway in regulating the tumor-immune microenvironment in dMMR/MSI colorectal cancer. Cancer Immunol Immunother 71, 2765–2776 (2022). https://doi.org/10.1007/s00262-022-03200-w

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