Skip to main content

Advertisement

SpringerLink
Log in

Clinical Outcomes and Immune Metrics in Intratumoral Basophil-Enriched Gastric Cancer Patients

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Accumulation of basophils has been reported in several malignancies. In gastric cancer, the relation between tumor-infiltrating basophils and patient overall survival and chemotherapeutic responsiveness still remains obscure.

Objective

We aimed to investigate the postoperative prognostic and predictive significance of basophils to survival outcomes and chemotherapeutic responsiveness in resectable gastric cancer.

Methods

The study enrolled two independent patient data sets with 448 gastric cancer patients overall. Basophils were evaluated with the use of immunohistochemistry (IHC) staining, and the correlation with clinicopathological characteristics, survival outcomes, and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) were investigated. Additionally, IHC was applied to characterize immune contexture in gastric cancer.

Results

In either the discovery or validation data sets, accumulated basophils indicated poorer prognosis, and tumor-infiltrating basophils were identified as an independent adverse prognostic factor by multivariate analysis. Furthermore, tumor-infiltrating basophils determined significantly inferior therapeutic responsiveness to fluorouracil-based ACT in patients with stage III tumors. In addition, the abundance of basophils was correlated with an immunoevasive contexture characterized by M2-polarized macrophage infiltration. Moreover, our findings indicated elevated interleukin-4 expression but decreased interferon-γ expression in the high-basophils subgroup.

Conclusions

Tumor-infiltrating basophils in gastric cancer were identified as an independent adverse prognosticator, and also predicted inferior chemotherapeutic responsiveness, which identified those patients in need of much more individualized postoperative adjuvant therapy and more stringent follow-up. Furthermore, the infiltration of basophils was associated with immunoevasive tumor microenvironment, which might be a potential immunotherapeutic target for gastric cancer.

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

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Feb 4 2021. https://doi.org/10.3322/caac.21660

    Article  PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32. https://doi.org/10.3322/caac.21338.

    Article  PubMed  Google Scholar 

  4. Fuchs CS, Mayer RJ. Gastric carcinoma. New England J Med. 1995;333(1):32–41. https://doi.org/10.1056/nejm199507063330107.

    Article  CAS  Google Scholar 

  5. De Vita F, Orditura M, Matano E, et al. A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer. 2005;92(9):1644–9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies: review article. Nature Reviews Cancer. 2003;3:330. https://doi.org/10.1038/nrc1074.

    Article  CAS  PubMed  Google Scholar 

  7. Karasuyama H, Mukai K, Obata K, Tsujimura Y, Wada T. Nonredundant roles of basophils in immunity. Ann Rev Immunol. 2011;29(1):45–69. https://doi.org/10.1146/annurev-immunol-031210-101257.

    Article  CAS  Google Scholar 

  8. Khodoun MV, Orekhova T, Potter C, Morris S, Finkelman FD. Basophils initiate IL-4 production during a memory T-dependent response. J Exp Med. 2004;200(7):857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Denzel A, Maus UA, Gomez MR, et al. Basophils enhance immunological memory responses. Nat Immunol. 2008;9(7):733–42. https://doi.org/10.1038/ni.1621.

    Article  CAS  PubMed  Google Scholar 

  10. Mukai K, Matsuoka K, Taya C, et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity. 2005;23(2):191–202. https://doi.org/10.1016/j.immuni.2005.06.011.

    Article  CAS  PubMed  Google Scholar 

  11. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9(3):310–8. https://doi.org/10.1038/ni1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Obata K, Mukai K, Tsujimura Y, et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood. 2007;110(3):913–20. https://doi.org/10.1182/blood-2007-01-068718.

    Article  CAS  PubMed  Google Scholar 

  13. Tsujimura Y, Obata K, Mukai K, et al. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity. 2008;28(4):581–9. https://doi.org/10.1016/j.immuni.2008.02.008.

    Article  CAS  PubMed  Google Scholar 

  14. Ohnmacht C, Schwartz C, Panzer M, Schiedewitz I, Naumann R, Voehringer D. Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity. 2010;33(3):364–74. https://doi.org/10.1016/j.immuni.2010.08.011.

    Article  CAS  PubMed  Google Scholar 

  15. Perrigoue JG, Saenz SA, Siracusa MC, et al. MHC class II-dependent basophil-CD4+ T cell interactions promote TH2 cytokine-dependent immunity. Nat Immunol. 2009;10(7):697–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yoshimoto T, Yasuda K, Tanaka H, et al. Basophils contribute to TH2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nat Immunol. 2009;10(7):706–12. https://doi.org/10.1038/ni.1737.

    Article  CAS  PubMed  Google Scholar 

  17. Sokol CL, Chu N-Q, Yu S, Nish SA, Laufer TM, Medzhitov R. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol. 2009;10(7):713–20. https://doi.org/10.1038/ni.1738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Matsushima T, Handa H, Yokohama A, et al. Prevalence and clinical characteristics of myelodysplastic syndrome with bone marrow eosinophilia or basophilia. Blood. 2003;101(9):3386. https://doi.org/10.1182/blood-2002-03-0947.

    Article  CAS  PubMed  Google Scholar 

  19. Wimazal F, Germing U, Kundi M, et al. Evaluation of the prognostic significance of eosinophilia and basophilia in a larger cohort of patients with myelodysplastic syndromes. Cancer. 2010;116(10):2372–81. https://doi.org/10.1002/cncr.25036.

    Article  PubMed  Google Scholar 

  20. Anthony HM. Blood basophils in lung cancer. Br J Cancer. 1982;45(2):209–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sektioglu IM, Carretero R, Bulbuc N, et al. Basophils promote tumor rejection via chemotaxis and infiltration of CD8+ T cells. Cancer Res. 2017;77(2):291–302. https://doi.org/10.1158/0008-5472.CAN-16-0993.

    Article  CAS  PubMed  Google Scholar 

  22. Cao Y, Liu H, Li H, et al. Association of O6-methylguanine-dna methyltransferase protein expression with postoperative prognosis and adjuvant chemotherapeutic benefits among patients with stage II or III gastric cancer. JAMA Surg. 2017;152(11):e173120. https://doi.org/10.1001/jamasurg.2017.3120.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang H, Liu H, Shen Z, et al. Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer. Ann Surg. 2018;267(2):311–8. https://doi.org/10.1097/sla.0000000000002058.

    Article  PubMed  Google Scholar 

  24. Wang JT, Li H, Zhang H, et al. Intratumoral IL17-producing cells infiltration correlate with antitumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer. Ann Oncol. 2019;30(2):266–73. https://doi.org/10.1093/annonc/mdy505.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang H, Li R, Cao Y, et al. Poor clinical outcomes and immunoevasive contexture in intratumoral IL-10-producing macrophages enriched gastric cancer patients. Ann Surg. 2020. https://doi.org/10.1097/SLA.0000000000004037.

    Article  PubMed  Google Scholar 

  26. Liu X, Cao Y, Li R, et al. Poor clinical outcomes of intratumoral dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin-positive macrophages associated with immune evasion in gastric cancer. Eur J Cancer. 2020;128:27–37. https://doi.org/10.1016/j.ejca.2020.01.002.

    Article  CAS  PubMed  Google Scholar 

  27. Shou Z-X, Jin X, Zhao Z-S. Upregulated expression of ADAM17 is a prognostic marker for patients with gastric cancer. Ann Surg. 2012;256(6):1014–22.

    Article  PubMed  Google Scholar 

  28. Clifford JL, Menter DG, Yang X, et al. Expression of protein mediators of type I interferon signaling in human squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prevent. 2000;9(9):993–7.

    CAS  Google Scholar 

  29. Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 2016;99(Pt B):186–96. https://doi.org/10.1016/j.addr.2015.07.007.

    Article  CAS  PubMed  Google Scholar 

  30. Seder RA, Paul WE, Dvorak AM, et al. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils. Proc Natl Acad Sci United States of America. 1991;88(7):2835–9.

    Article  CAS  Google Scholar 

  31. Piccinni MP, Macchia D, Parronchi P, et al. Human bone marrow non-B, non-T cells produce interleukin 4 in response to cross-linkage of Fc epsilon and Fc gamma receptors. Proc Natl Acad Sci United States of America. 1991;88(19):8656–60.

    Article  CAS  Google Scholar 

  32. Schroeder JT, MacGlashan DW, Lichtenstein LM. Human basophils: mediator release and cytokine production. Adv Immunol. 2001;77:93–122.

    Article  CAS  PubMed  Google Scholar 

  33. Ohnmacht C, Voehringer D. Basophils protect against reinfection with hookworms independently of mast cells and memory Th2 cells. J Immunol. 2009;184(1):344. https://doi.org/10.4049/jimmunol.0901841.

    Article  CAS  PubMed  Google Scholar 

  34. Paul WE, Zhu J. How are TH2-type immune responses initiated and amplified? Nat Rev Immunol. 2010;10(4):225–35. https://doi.org/10.1038/nri2735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ho IC, Tai T-S, Pai S-Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125–35. https://doi.org/10.1038/nri2476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. De Monte L, Wörmann S, Brunetto E, et al. Basophil recruitment into tumor-draining lymph nodes correlates with Th2 inflammation and reduced survival in pancreatic cancer patients. Cancer Res. 2016;76(7):1792. https://doi.org/10.1158/0008-5472.CAN-15-1801-T.

    Article  CAS  PubMed  Google Scholar 

  37. Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther. 1990;48(3):381–95. https://doi.org/10.1016/0163-7258(90)90056-8.

    Article  CAS  PubMed  Google Scholar 

  38. Major PP, Egan E, Herrick D, Kufe DW. 5-Fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Res. 1982;42(8):3005.

    CAS  PubMed  Google Scholar 

  39. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8. https://doi.org/10.1038/nrc1074.

    Article  CAS  PubMed  Google Scholar 

  40. Todaro M, Alea MP, Di Stefano AB, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1(4):389–402. https://doi.org/10.1016/j.stem.2007.08.001.

    Article  CAS  PubMed  Google Scholar 

  41. Nevala WK, Vachon CM, Leontovich AA, Scott CG, Thompson MA, Markovic SN. Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res. 2009;15(6):1931. https://doi.org/10.1158/1078-0432.CCR-08-1980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guenova E, Watanabe R, Teague JE, et al. TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin Cancer Res. 2013;19(14):3755–63. https://doi.org/10.1158/1078-0432.CCR-12-3488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wenzel L, Osann K, Hsieh S, Tucker JA, Monk BJ, Nelson EL. Psychosocial telephone counseling for survivors of cervical cancer: results of a randomized biobehavioral trial. J Clin Oncol. 2015;33(10):1171–9. https://doi.org/10.1200/JCO.2014.57.4079.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Todaro M, Lombardo Y, Francipane MG, et al. Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ. 2008;15(4):762–72.

    Article  CAS  PubMed  Google Scholar 

  45. Nagai H, Miyaki D, Matsui T, et al. Th1/Th2 balance: an important indicator of efficacy for intra-arterial chemotherapy. Cancer Chemother Pharmacol. 2008;62(6):959–63. https://doi.org/10.1007/s00280-008-0685-y.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang H, Wang X, Shen Z, Xu J, Qin J, Sun Y. Infiltration of diametrically polarized macrophages predicts overall survival of patients with gastric cancer after surgical resection. Gastric Cancer. 2015;18(4):740–50. https://doi.org/10.1007/s10120-014-0422-7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Peipei Zhang (Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China) for their excellent help with the pathological technology.

Funding

This study was funded by grants from the National Natural Science Foundation of China (31770851, 81871930, 81902402, 81902901, 81972219) and Shanghai Sailing Program (17YF1402200, 18YF1404600, 19YF1407500).

Author information

Author notes

  1. Xudong He, Yifan Cao, Yun Gu, and Hanji Fang contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Xudong He PhD, Yun Gu MD, Hanji Fang MD, Xin Liu PhD, Kunpeng Lv PhD, Yuchao Fei MD & Jiejie Xu MD

  2. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Yifan Cao MD, Kuan Yu MD, Chao Lin MD, Hao Liu MD, Heng Zhang MD, He Li MD, Ruochen Li MD & Hongyong He MD

  3. Department of Gastric Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China

    Jieti Wang MD

Authors
  1. Xudong He PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yifan Cao MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun Gu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanji Fang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jieti Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xin Liu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kunpeng Lv PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kuan Yu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuchao Fei MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chao Lin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hao Liu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Heng Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. He Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jiejie Xu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ruochen Li MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hongyong He MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XH, YC, YG and KJ undertook acquisition of data, analysis and interpretation of data, statistical analysis, and drafting of the manuscript. JW, XL, KL, HF, KJ, YF, CL, HL, HZ, HL, JX provided technical and material support. RL and HH undertook study concept and design, analysis and interpretation of data, and drafting of the manuscript, obtained funding, and provided study supervision. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ruochen Li MD or Hongyong He MD.

Ethics declarations

Disclosures

Xudong He, Yifan Cao, Yun Gu, Hanji Fang, Jieti Wang, Xin Liu, Kunpeng Lv, Kuan Yu, Yuchao Fei, Chao Lin, Hao Liu, Heng Zhang, He Li, Jiejie Xu, Ruochen Li, and Hongyong He declare they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (pdf 2145 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, X., Cao, Y., Gu, Y. et al. Clinical Outcomes and Immune Metrics in Intratumoral Basophil-Enriched Gastric Cancer Patients. Ann Surg Oncol 28, 6439–6450 (2021). https://doi.org/10.1245/s10434-021-09815-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-021-09815-0

Search

Navigation