Abstract
The latest research confirms that cytotoxic lymphocytes rely on pyroptosis to kill tumor cells, suggesting that pyroptosis plays a vital role in immune response. However, the influence of pyroptosis on tumor microenvironment (TME) remodeling and immunotherapy is still unclear. We analyzed the variations in the expression of 28 pyroptosis-related molecules in pan-cancer tissues and normal tissues and the influence of genome changes. We investigated 2,214 bladder cancer samples and determined that there are three pyroptosis phenotypes in bladder cancer, and there are significant differences in cell infiltration characteristics in different pyroptosis phenotypes. Phenotypes with high expression of pyroptosis-related molecules are “hot tumors” with better immune function. We used a principal component analysis to measure the level of pyroptosis in patients with PyroScore, and confirmed that the PyroScore can predict the prognosis of bladder cancer patients, the sensitivity of the immune phenotype to chemotherapy, and the response to immunotherapy. Patients with a high PyroScore are more sensitive to chemotherapeutics such as cisplatin and gemcitabine, and have a better prognosis (HR = 0.7; 95%CI = 0.51–0.97, P = 0.041). Our study suggests a significant correlation between the expression imbalance of pyroptosis-related molecules and genome variation in various cancers and suggests pyroptosis plays an important role in modeling the TME. Evaluating pyroptosis modification patterns contributes to enhancing our understanding of TME infiltration and can guide more effective immunotherapy strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rouprêt M, Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, et al. European association of urology guidelines on upper urinary tract urothelial carcinoma: 2020 update. Eur Urol. 2021;79:62–79.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:20–249.
Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.
Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312–22.
Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc. 2019;94:1321–9.
Chen X, Chen H, He D, Cheng Y, Zhu Y, Xiao M, et al. Analysis of tumor microenvironment characteristics in bladder cancer: implications for immune checkpoint inhibitor therapy. Front Immunol. 2021;12:672158.
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. P Natl Acad Sci USA. 2010;107:4275–80.
Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol. 2016;27:1482–92.
Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2019. https://doi.org/10.1126/science.aar3593.
Rosenbaum SR, Wilski NA, Aplin AE. Fueling the fire: inflammatory forms of cell death and implications for cancer Immunotherapy. Cancer Disco. 2021;11:266–81.
Zhou Z, He H, Wang K, Shi X, Wang Y, Su Y et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science. 2020. https://doi.org/10.1126/science.aaz7548.
Xii G, Gao J, Wan B, Zhan P, Xu W, Lv T. GSDMD is required for effector CD8(+) T cell responses to lung cancer cells. Int Immunopharmacol. 2019;74:74.
Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579:415–20.
Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W, et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature. 2020;579:421–6.
Van Opdenbosch N, Lamkanfi M. Caspases in cell death, inflammation, and disease. Immunity. 2019;50:1352–64.
Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109.
Broz P, Pelegrin P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:143–57.
Qin X, Li J, Hu W, Yang J. Machine learning k-means clustering algorithm for interpolative separable density fitting to accelerate hybrid functional calculations with numerical atomic orbitals. J Phys Chem A. 2020;124:10066–74.
Ritchieitchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
Finotello F, Mayer C, Plattner C, Laschober G, Rieder D, Hackl H, et al. Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med. 2019;11:34.
Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17:174.
Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 2017;18:220.
Becht E, Giraldo NA, Lacroix L, Buttard B. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016. https://doi.org/10.1186/s13059-016-1070-5.
Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al. A molecular classification of muscle-invasive bladder cancer. Eur Urol. 2020;77:420–33.
Xiao Y, Ma D, Zhao S, Suo C, Shi J, Xue MZ, et al. Multi-omics profiling reveals distinct microenvironment characterization and suggests immune escape mechanisms of triple-negative breast cancer. Clin Cancer Res. 2019;25:5002–14.
Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.
Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl J Med. 2012;366:2443–54.
Decout A, Katz JD, Venkatraman S, Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021;21:548–69.
Bode C, Poth JM, Fox M, Schulz S, Klinman DM, Latz E et al. Cytosolic d-type CpG-oligonucleotides induce a type i interferon response by activating the cGAS-STING signaling pathway. Eur J Immunol. 2021;51:1686–97.
Hou J, Zhao R, Xia W, Chang CW, You Y, Hsu JM, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol. 2020;22:1264–75.
An H, Heo JS, Kim P, Lian Z, Lee S, Park J.et al. Tetraarsenic hexoxide enhances generation of mitochondrial ROS to promote pyroptosis by inducing the activation of caspase-3/GSDME in triple-negative breast cancer cells. Cell Death Dis. 2021;12:159.
Jiang M, Qi L, Li L, Li Y. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer. Cell Death Disco. 2020;6:112.
Shen X, Wang H, Weng C, Jiang H, Chen J. Caspase 3/GSDME-dependent pyroptosis contributes to chemotherapy drug-induced nephrotoxicity. Cell Death Dis. 2021;12:186.
Zheng M, Karki R, Vogel P, Kanneganti TD. Caspase-6 Is a key regulator of innate immunity, inflammasome activation, and host defense. Cell. 2020;181:674–87.e13.
Acknowledgements
We acknowledge the TCGA, GEO, and the ArrayExpress databases and their contributors. We would like to thank TissueGnostics Aisa Pacific limited for their technical support, And the help of Hongzhe Sun and Xiaojing Liu, the technical engineer.
Funding
This work was supported by the National Natural Science Foundation of China (81874137), the science and technology innovation Program of Hunan Province (2020RC4011), the Outstanding Youth Foundation of Hunan Province (2018JJ1047), the Hunan Province Science and Technology Talent Promotion Project (2019TJ-Q10), Young Scholars of “Furong Scholar Program” in Hunan Province, and the Wisdom Accumulation and Talent Cultivation Project of the Third xiangya hosipital of Central South University (BJ202001).
Author information
Authors and Affiliations
Contributions
Conceptualization, XC; methodology, XC and HC; investigation, XC, HC, HY, KZ, YZ, DH, YZ, YC, RL, and RX; writing—original drafts, XC; writing—review & editing, XC and HC; funding acquisition, KC; supervision, KC.
Corresponding author
Ethics declarations
COMPETING INTERESTS
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Chen, X., Chen, H., Yao, H. et al. Turning up the heat on non-immunoreactive tumors: pyroptosis influences the tumor immune microenvironment in bladder cancer. Oncogene 40, 6381–6393 (2021). https://doi.org/10.1038/s41388-021-02024-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-021-02024-9
This article is cited by
-
Screening of novel tumor-associated antigens for lung adenocarcinoma mRNA vaccine development based on pyroptosis phenotype genes
BMC Cancer (2024)
-
Pyroptosis patterns influence the clinical outcome and immune microenvironment characterization in HPV-positive head and neck squamous cell carcinoma
Infectious Agents and Cancer (2023)
-
Identification and validation of pyroptosis-related gene landscape in prognosis and immunotherapy of ovarian cancer
Journal of Ovarian Research (2023)
-
Integrated machine learning identifies epithelial cell marker genes for improving outcomes and immunotherapy in prostate cancer
Journal of Translational Medicine (2023)
-
A novel defined pyroptosis-related gene signature predicts prognosis and correlates with the tumour immune microenvironment in lung adenocarcinoma
Scientific Reports (2023)