Skip to main content
SpringerLink
Log in

An immunogenic cell death-related signature predicts prognosis and immunotherapy response in stomach adenocarcinoma

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

The immunogenic cell death (ICD) is a specific type of regulatory cell death (RCD), which induces adaptive immunity against antigens of dead cells. ICDs have received increasing attention for their potential role in tumor microenvironment reprogramming and immunotherapy. However, the relationship between ICD-related features and stomach adenocarcinoma (STAD) prognosis, immune cell infiltration and immunotherapy remains unclear. Patients were divided into different ICD-related subtypes by consensus clustering. The differences in prognosis, Tumor microenvironment (TME), and immune checkpoint expression between different ICD-related subtypes were systematically assessed. Additionally, we constructed an ICD-related gene risk score (ICDRS). We systematically analyzed the correlation between ICDRS and prognosis, TME, immunotherapy response and drug sensitivity of gastric cancer. In addition, we explored the role of TGM2 in promoting gastric cancer progression through in vitro experiments. We identified three ICD-associated subtypes by consensus clustering. The ICD gene was highly expressed in Cluster B. Compared with the other two subtypes, Cluster B had better prognosis, higher immune response signaling activity, massive immune cell infiltration and lower tumor purity. Immune checkpoint (ICP) and human leukocyte antigen (HLA) related genes were also highly expressed in Cluster B. In addition, we found that ICDRS is an effective indicator for predicting the prognosis and immune efficacy of STAD. The low ICDRS group has the characteristics of good prognosis, high tumor mutation burden (TMB), high microsatellite instability (MSI), and sensitivity to immunotherapy, while the high ICDRS group is prone to immune escape and immunotherapy resistance. In addition, we found that down-regulating TGM2 gene can inhibit the proliferation and migration of gastric cancer cells through in vitro experiments. Our study found that the model based on ICD features is helpful to clarify the TME characteristics of STAD, and has important clinical significance for evaluating the prognosis and immunotherapy response of STAD patients. TGM2 plays an important role in the progression of STAD, suggesting that TGM2 can be used as a new target for the treatment of STAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are available at TCGA-STAD [GDC (GDC (cancer.gov)], GSE84437 [GEO Accession viewer (nih.gov)] and Supplementary Materials.

Abbreviations

ICD:

Immunogenic cell death

RCD:

Regulatory cell death

TME:

Tumor microenvironment

STAD:

Stomach adenocarcinoma

GC:

Gastric cancer

ICDRS:

ICD-related gene risk score

TMB:

Tumor mutation burden

MSI:

Microsatellite instability

ICIs:

Immune checkpoint inhibitors

DAMPs:

Damage-associated molecular patterns

TCGA:

The Cancer Genome Atlas

GEO:

Gene Expression Omnibus

GSVA:

Gene set variation analysis

ssGSEA:

Single-sample gene set enrichment analysis

DEGs:

Differentially expressed genes

OS:

Overall survival time

TIDE:

Tumor immune dysfunction and exclusion

ImmuCellIA:

Abundance of immune cell infiltrates

RNAss:

RNA stemness score

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  PubMed  Google Scholar 

  2. Gambardella V, Castillo J, Tarazona N, Gimeno-Valiente F, Martínez-Ciarpaglini C, Cabeza-Segura M et al (2020) The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target. Cancer Treat Rev 86:102015

    Article  CAS  PubMed  Google Scholar 

  3. Russo AE, Strong VE (2019) Gastric cancer etiology and management in Asia and the West. Annu Rev Med 70:353–367

    Article  CAS  PubMed  Google Scholar 

  4. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K et al (2020) Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26(4):566–576

    Article  CAS  PubMed  Google Scholar 

  5. Sheih A, Voillet V, Hanafi LA, DeBerg HA, Yajima M, Hawkins R et al (2020) Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy. Nat Commun 11(1):219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Riley RS, June CH, Langer R, Mitchell MJ (2019) Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov 18(3):175–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang Y, Zhang Z (2020) The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol 17(8):807–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science (New York, NY) 359(6382):1350–1355

    Article  CAS  Google Scholar 

  9. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nagarsheth N, Wicha MS, Zou W (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17(9):559–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shi Y, Lammers T (2019) Combining Nanomedicine and Immunotherapy. Acc Chem Res 52(6):1543–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smyth MJ, Ngiow SF, Ribas A, Teng MW (2016) Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13(3):143–158

    Article  CAS  PubMed  Google Scholar 

  13. Jin MZ, Jin WL (2020) The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther 5(1):166

    Article  PubMed  PubMed Central  Google Scholar 

  14. Li Z, Lai X, Fu S, Ren L, Cai H, Zhang H et al (2022) Immunogenic cell death activates the tumor immune microenvironment to boost the immunotherapy efficiency. Adv Sci 9(22):e2201734

    Article  Google Scholar 

  15. Fucikova J, Kepp O, Kasikova L, Petroni G, Yamazaki T, Liu P et al (2020) Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis 11(11):1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB et al (2020) Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immunother Cancer 8(1):e000337

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jin MZ, Wang XP (2021) Immunogenic cell death-based cancer vaccines. Front Immunol 12:697964

    Article  PubMed  PubMed Central  Google Scholar 

  18. Alzeibak R, Mishchenko TA, Shilyagina NY, Balalaeva IV, Vedunova MV, Krysko DV (2021) Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future. J Immunother Cancer 9(1):e001926

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lau TS, Chan LKY, Man GCW, Wong CH, Lee JHS, Yim SF et al (2020) Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4/IKK2/SNARE-dependent exocytosis. Cancer Immunol Res 8(8):1099–1111

    Article  CAS  PubMed  Google Scholar 

  20. Wang X, Wu S, Liu F, Ke D, Wang X, Pan D et al (2021) An Immunogenic cell death-related classification predicts prognosis and response to immunotherapy in head and neck squamous cell carcinoma. Front Immunol 12:781466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clifton GT, Rothenberg M, Ascierto PA, Begley G, Cecchini M, Eder JP et al (2023) Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop. J Immunother Cancer 11(6):e006773

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu YT, Sun ZJ (2021) Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics 11(11):5365–5386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15(11):669–682

    Article  CAS  PubMed  Google Scholar 

  24. Kroemer G, Galassi C, Zitvogel L, Galluzzi L (2022) Immunogenic cell stress and death. Nat Immunol 23(4):487–500

    Article  CAS  PubMed  Google Scholar 

  25. Ahmed A, Tait SWG (2020) Targeting immunogenic cell death in cancer. Mol Oncol 14(12):2994–3006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013) Immunogenic cell death in cancer therapy. Annu Rev Immunol 31:51–72

    Article  CAS  PubMed  Google Scholar 

  27. Li Y, Zhang H, Li Q, Zou P, Huang X, Wu C et al (2020) CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett 495:12–21

    Article  CAS  PubMed  Google Scholar 

  28. Duan X, Chan C, Lin W (2019) Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew Chem Int Ed Engl 58(3):670–680

    Article  CAS  PubMed  Google Scholar 

  29. Fu L, Zhou X, He C (2021) Polymeric nanosystems for immunogenic cell death-based cancer immunotherapy. Macromol Biosci 21(7):e2100075

    Article  PubMed  Google Scholar 

  30. Hsieh YF, Liu GY, Lee YJ, Yang JJ, Sándor K, Sarang Z et al (2013) Transglutaminase 2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ homeostasis via cross-linking RAP1GDS1. PLoS One 8(12):e81516

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li C, Cai J, Ge F, Wang G (2018) TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma. Int J Mol Med 42(4):1799–1808

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fok JY, Ekmekcioglu S, Mehta K (2006) Implications of tissue transglutaminase expression in malignant melanoma. Mol Cancer Ther 5(6):1493–1503

    Article  CAS  PubMed  Google Scholar 

  33. Park KS, Kim HK, Lee JH, Choi YB, Park SY, Yang SH et al (2010) Transglutaminase 2 as a cisplatin resistance marker in non-small cell lung cancer. J Cancer Res Clin Oncol 136(4):493–502

    Article  CAS  PubMed  Google Scholar 

  34. Yang P, Yu D, Zhou J, Zhuang S, Jiang T (2019) TGM2 interference regulates the angiogenesis and apoptosis of colorectal cancer via Wnt/β-catenin pathway. Cell Cycle (Georgetown, Tex) 18(10):1122–1134

    Article  CAS  PubMed  Google Scholar 

  35. Agnihotri N, Kumar S, Mehta K (2013) Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer. Breast Cancer Res 15(1):202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Naselsky W, Adhikary G, Shrestha S, Chen X, Ezeka G, Xu W et al (2022) Transglutaminase 2 enhances hepatocyte growth factor signaling to drive the mesothelioma cancer cell phenotype. Mol Carcinog 61(6):537–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao Q, Cao L, Guan L, Bie L, Wang S, Xie B et al (2019) Immunotherapy for gastric cancer: dilemmas and prospect. Brief Funct Genom 18(2):107–112

    Article  CAS  Google Scholar 

  38. Vrána D, Matzenauer M, Neoral Č, Aujeský R, Vrba R, Melichar B et al (2018) From tumor immunology to immunotherapy in gastric and esophageal cancer. Int J Mol Sci 20(1):13

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L (2016) Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 27(8):1482–1492

    Article  CAS  PubMed  Google Scholar 

  40. Lytle NK, Barber AG, Reya T (2018) Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer 18(11):669–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bajaj J, Diaz E, Reya T (2020) Stem cells in cancer initiation and progression. J Cell Biol 219(1):e201911053

    Article  PubMed  Google Scholar 

  42. Ferguson LP, Diaz E, Reya T (2021) The role of the microenvironment and immune system in regulating stem cell fate in cancer. Trends Cancer 7(7):624–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to express our appreciation to TCGA-STAD [GDC (cancer.gov)] and GEO databases (https://www.ncbi.nlm.nih.gov/geo/) for providing the open-access databases utilized in this research study.

Funding

This research was funded by the Project of the Jiangxi Provincial Education Department of Science and Technology Research (Grant Number: GJJ2200234).

Author information

Author notes

  1. Zitao Liu, Liang Sun and Xingyu Peng have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, People’s Republic of China

    Zitao Liu, Liang Sun, Xingyu Peng, Sicheng Liu, Zhengming Zhu & Chao Huang

Authors
  1. Zitao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xingyu Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sicheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhengming Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZTL, LS and XYP conceived and designed the study, CH and SCL collected the data and clinical specimens. ZTL and LS analyzed the data, searched the literature and evaluated the quality. ZMZ, ZTL, and CH prepared the first draft of the manuscript and corrected it. All the authors have read the manuscript and agreed to the final version of the manuscript.

Corresponding authors

Correspondence to Zhengming Zhu or Chao Huang.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University, and all patients signed informed consent.

Consent for publication

Not applicable.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Z., Sun, L., Peng, X. et al. An immunogenic cell death-related signature predicts prognosis and immunotherapy response in stomach adenocarcinoma. Apoptosis 28, 1564–1583 (2023). https://doi.org/10.1007/s10495-023-01879-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-023-01879-5

Keywords

Search

Navigation