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Bacillus Calmette-Guerin induces CD8+ T cell infiltration and suppresses tumor progression in microsatellite stable colorectal cancer by downregulating ARID1A

Cancer Gene Therapy volume 32, pages 1319–1329 (2025)Cite this article

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Abstract

Neoadjuvant immunotherapy demonstrates limited efficacy in microsatellite-stable (MSS) colorectal cancer (CRC). In vivo observations reveal that Bacillus Calmette–Guérin (BCG) can inhibit the progression of MSS-CRC and downregulate ARID1A in both in vivo and in vitro settings. Through the analysis of clinical samples, in vivo and in vitro models, and bioinformatics, we found that the low expression of ARID1A promotes tumor growth in vitro; however, in vivo, it enhances CD8+ T cell infiltration in MSS-CRC tissues while inhibiting tumor growth. Further investigation revealed that BCG downregulates ARID1A via the TLR4/NF-κB pathway, leading to the downregulation of MLH1 and PMS2 and subsequent alterations in MMR function in MSS-CRC. This cascade enhances antigen presentation, promotes CD8+ T cell infiltration, and contributes to tumor suppression.

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Fig. 1: BCG inhibits the progression of MSS-CRC and downregulates the expression of ARID1A within tumors.
Fig. 2: ARID1A inhibits the progression of CRC.
Fig. 3: Bioinformatics analysis of the correlation between ARID1A expression and CD8 + T cell infiltration levels.
Fig. 4: Analysis of cell communication pathways in MSS-CRC with differential expression of ARID1A.
Fig. 5: Knockdown of ARID1A inhibits the progression of MSS-CRC in vivo.
Fig. 6: BCG downregulates ARID1A through the TLR4/NF-κB axis, subsequently leading to the downregulation of MLH1 and PMS2 in MSS-CRC.

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Data availability

The data generated in this study are available upon request from the corresponding author.

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.

    Article  PubMed  Google Scholar 

  3. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. Jama. 2021;325:669–85.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang X, Wu T, Cai X, Dong J, Xia C, Zhou Y, et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: new strategies and unveiled opportunities. Front Immunol. 2022;13:795972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhu J, Lian J, Xu B, Pang X, Ji S, Zhao Y, et al. Neoadjuvant immunotherapy for colorectal cancer: right regimens, right patients, right directions? Front Immunol. 2023;14:1120684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Picard E, Verschoor CP, Ma GW, Pawelec G. Relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer. Front Immunol. 2020;11:369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lin A, Zhang J, Luo P. Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol. 2020;11:2039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kasi PM, Hidalgo M, Jafari MD, Yeo H, Lowenfeld L, Khan U, et al. Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. Oncogene. 2023;42:3252–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li J, Wu C, Hu H, Qin G, Wu X, Bai F, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell. 2023;41:1152–1169.e7.

    Article  PubMed  Google Scholar 

  10. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26:566–76.

    Article  CAS  PubMed  Google Scholar 

  11. Qu M, Zhou X, Li H. BCG vaccination strategies against tuberculosis: updates and perspectives. Hum Vaccines Immunother. 2021;17:5284–95.

    Article  Google Scholar 

  12. Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur Urol. 2022;81:75–94.

    Article  PubMed  Google Scholar 

  13. Moreo E, Jarit-Cabanillas A, Robles-Vera I, Uranga S, Guerrero C, Gómez AB, et al. Intravenous administration of BCG in mice promotes natural killer and T cell-mediated antitumor immunity in the lung. Nat Commun. 2023;14:6090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Morra ME, Kien ND, Elmaraezy A, Abdelaziz OAM, Elsayed AL, Halhouli O, et al. Early vaccination protects against childhood leukemia: a systematic review and meta-analysis. Sci Rep. 2017;7:15986.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kremenovic M, Schenk M, Lee DJ. Clinical and molecular insights into BCG immunotherapy for melanoma. J Intern Med. 2020;288:625–40.

    Article  CAS  PubMed  Google Scholar 

  16. Olbert PJ, Kesch C, Henrici M, Subtil FS, Honacker A, Hegele A, et al. TLR4- and TLR9-dependent effects on cytokines, cell viability, and invasion in human bladder cancer cells. Urol Oncol. 2015;33:110.e19–27.

    Article  CAS  PubMed  Google Scholar 

  17. Shetab Boushehri MA, Lamprecht A. TLR4-based immunotherapeutics in cancer: a review of the achievements and shortcomings. Mol Pharm. 2018;15:4777–800.

    Article  CAS  PubMed  Google Scholar 

  18. Jin F, Yang Z, Shao J, Tao J, Reißfelder C, Loges S, et al. ARID1A mutations in lung cancer: biology, prognostic role, and therapeutic implications. Trends Mol Med. 2023;29:646–58.

    Article  CAS  PubMed  Google Scholar 

  19. Mullen J, Kato S, Sicklick JK, Kurzrock R. Targeting ARID1A mutations in cancer. Cancer Treat Rev. 2021;100:102287.

    Article  CAS  PubMed  Google Scholar 

  20. Jiang T, Chen X, Su C, Ren S, Zhou C. Pan-cancer analysis of ARID1A alterations as biomarkers for immunotherapy outcomes. J Cancer. 2020;11:776–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maxwell MB, Hom-Tedla MS, Yi J, Li S, Rivera SA, Yu J, et al. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity. Cell. 2024;187:3390–3408.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee LH, Sadot E, Ivelja S, Vakiani E, Hechtman JF, Sevinsky CJ, et al. ARID1A expression in early stage colorectal adenocarcinoma: an exploration of its prognostic significance. Hum Pathol. 2016;53:97–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chou A, Toon CW, Clarkson A, Sioson L, Houang M, Watson N, et al. Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency. Hum Pathol. 2014;45:1697–703.

    Article  CAS  PubMed  Google Scholar 

  24. Lee SY, Kim DW, Lee HS, Ihn MH, Oh HK, Park DJ, et al. Loss of AT-rich interactive domain 1A expression in gastrointestinal malignancies. Oncology. 2015;88:234–40.

    Article  CAS  PubMed  Google Scholar 

  25. Wei XL, Wang DS, Xi SY, Wu WJ, Chen DL, Zeng ZL, et al. Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer. World J Gastroenterol. 2014;20:18404–12.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xu HX, Zhu P, Zheng YY, Zhang X, Chen YQ, Qiao LC, et al. Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort. Am J Cancer Res. 2020;10:3920–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang J, Li R, He Y, Yi Y, Wu H, Liang Z. Next-generation sequencing reveals heterogeneous genetic alterations in key signaling pathways of mismatch repair deficient colorectal carcinomas. Mod Pathol. 2020;33:2591–601.

    Article  CAS  PubMed  Google Scholar 

  28. Sun D, Zhao H, Zhou H, Tao J, Li T, Zhu J, et al. ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma. Transl Oncol. 2023;33:101685.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Heinze K, Nazeran TM, Lee S, Krämer P, Cairns ES, Chiu DS, et al. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas. J Pathol. 2022;256:388–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24:556–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Awadalla A, Zahran MH, Abol-Enein H, Zekri AN, Elbaset MA, Ahmed AE, et al. Identification of different miRNAs and their relevant miRNA targeted genes involved in sister chromatid cohesion and segregation (SCCS)/chromatin remodeling pathway on T1G3 urothelial carcinoma (UC) response to BCG immunotherapy. Clin Genitourin Cancer. 2022;20:e181–e189.

    Article  PubMed  Google Scholar 

  32. Bacon JVW, Müller DC, Ritch E, Annala M, Dugas SG, Herberts C, et al. Somatic features of response and relapse in non-muscle-invasive bladder cancer treated with Bacillus Calmette–Guérin immunotherapy. Eur Urol Oncol. 2022;5:677–86.

    Article  PubMed  Google Scholar 

  33. Xia QD, Sun JX, Yao ZP, Lu JL, Liu CQ, Xu JZ, et al. The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG. NPJ Precis Oncol. 2024;8:216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Emiloju OE, Sinicrope FA. Neoadjuvant immune checkpoint inhibitor therapy for localized deficient mismatch repair colorectal cancer: a review. JAMA Oncol. 2023;9:1708–15.

    Article  PubMed  Google Scholar 

  35. Jin Z, Sinicrope FA. Mismatch repair-deficient colorectal cancer: building on checkpoint blockade. J Clin Oncol. 2022;40:2735–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yu I, Dakwar A, Takabe K. Immunotherapy: recent advances and its future as a neoadjuvant, adjuvant, and primary treatment in colorectal cancer. Cells. 2023;12:258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dobruch J, Oszczudlowski M. Bladder cancer: current challenges and future directions. Medicina (Kaunas). 2021;57:749.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kim YM, Choi JO, Cho YJ, Hong BK, Shon HJ, Kim BJ, et al. Mycobacterium potentiates protection from colorectal cancer by gut microbial alterations. Immunology. 2023;168:493–510.

    Article  CAS  PubMed  Google Scholar 

  39. Moradi-Marjaneh R, Hassanian SM, Fiuji H, Soleimanpour S, Ferns GA, Avan A, et al. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol. 2018;233:5613–22.

    Article  CAS  PubMed  Google Scholar 

  40. Fontana B, Gallerani G, Salamon I, Pace I, Roncarati R, Ferracin M. ARID1A in cancer: friend or foe? Front Oncol. 2023;13:1136248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S. Targeting PI3K/AKT/mTOR and MAPK signaling pathways in gastric cancer. Int J Mol Sci. 2024;25:1848.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope et al. Integrated genomic and molecular characterization of cervical cancer. Nature. 2017;543:378–84.

  43. Zheng Y, Li Y, Ran X, Wang D, Zheng X, Zhang M, et al. Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway. Cell Mol Life Sci. 2022;79:311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by National Science and Technology Innovation 2030 Major Program (2023ZD0500103), National Natural Science Foundation of China (82472895), Guangzhou Basic and Applied Basic Research Foundation (2024A04J6605 and SL2023A04J02310) and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (pdjh2024b095).

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Author notes

  1. These authors contributed equally: Zhiyue Xie, Nan Peng, Zhihua Pan.

Authors and Affiliations

  1. Department of Pathology, The Eighth Affiliated Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China

    Zhiyue Xie, Rui Li & Liang Zhao

  2. Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Zhiyue Xie, Nan Peng, Yun Feng, Yihan Wu & Liang Zhao

  3. Department of Gastroenterology, The Second People’s Hospital of Foshan, Foshan, China

    Zhihua Pan

  4. Department of Pathology, Raoping County Traditional Chinese Medicine Hospital, Chaozhou, China

    Yansheng Yang

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Contributions

Zhiyue Xie: Carry out the experiments and write the original draft. Nan Peng and Zhihua Pan: Collect data and prepared figures. Yun Feng and Yihan Wu: Analyze the data. Yansheng Yang and Rui Li: Assist in tissue sample collection and data analysis. Liang Zhao: Direct the study, review, edit, supervise and fund acquisition. All authors contributed to the writing and revision of the manuscript and approved its submission.

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Correspondence to Liang Zhao.

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Xie, Z., Peng, N., Pan, Z. et al. Bacillus Calmette-Guerin induces CD8+ T cell infiltration and suppresses tumor progression in microsatellite stable colorectal cancer by downregulating ARID1A. Cancer Gene Ther 32, 1319–1329 (2025). https://doi.org/10.1038/s41417-025-00964-y

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