Abstract
This study aimed to further explore the clinicopathological correlation of B cell infiltration in gastric cancer (GC) and its impact on prognostic. By immunohistochemical method, CD20+ B cells, CD3+ T cells, CD66b+ tumor-associated neutrophils, CD163+ tumor-associated macrophages, and CD57+ natural killer cells were analyzed in consecutive sections of 584 GC tissues and 69 normal adjacent tissues. Kaplan–Meier and Cox regression analyses determined the relationship between clinical relevance or prognosis and B cell infiltration. The correlation between total B cell infiltration and various T cell subtype infiltration in GC tissues from 407 patients in the TCGA data was also analyzed. Kaplan–Meier and Cox regression analyses determined the effects of total B cell infiltration and various B cell subtype infiltration on the prognosis of patients with GC. The infiltration level of CD20+ B cells was positively correlated with that of T cells (risk ratio [RR] = 0.0930), especially CD4+ T cells and CD8+ T cells (P < 0.05). A high level of CD20+ B cell infiltration was significantly associated with low lymph node involvement and low TNM stage (P < 0.05). High levels of CD20+ B cell infiltration were significantly associated with improvements in overall survival and disease-free survival. Univariate Cox regression and multivariate Cox regression analysis showed that CD20+ B cell infiltration was an independent protective factor of prognosis. Higher levels of class-switched memory B cell and plasma cell also reflected better overall survival, and class-switched memory B cell and plasma cell were independent protective factors for prognosis. The findings indicate that B cell infiltration in GC, especially switched memory B cells and plasma cells, has a significant effect on tumor progression and prognosis.
Similar content being viewed by others
References
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res. 2008;14:5220–7.
Berntsson J, Nodin B, Eberhard J, Micke P, Jirstrom K. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer. 2016;139:1129–39.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet. 2004;41:508–17.
Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10:7252–9.
Chen Z, Gerhold-Ay A, Gebhard S, Boehm D, Solbach C, Lebrecht A, et al. Immunoglobulin kappa C predicts overall survival in node-negative breast cancer. PLoS One. 2012;7:e44741.
Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer. 2000;88:1739–57.
Demina I, Zerkalenkova E, Illarionova O, Olshanskaya Y, Verzhbitskaya T, Semchenkova A, et al. Heterogeneity of childhood acute leukemia with mature B-cell immunophenotype. J Cancer Res Clin Oncol. 2019;145:2803–11.
DiLillo DJ, Yanaba K, Tedder TF. B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol. 2010;184:4006–16.
Gonzalez CA, Sala N, Rokkas T. Gastric cancer: epidemiologic aspects. Helicobacter. 2013;18(Suppl 1):34–8.
Hennequin A, Derangère V, Boidot R, Apetoh L, Vincent J, Orry D, et al. Tumor infiltration by Tbet+ effector T cells and CD20+ B cells is associated with survival in gastric cancer patients. Oncoimmunology. 2016;5:e1054598.
Hu HT, Ai X, Lu M, Song Z, Li H. Characterization of intratumoral and circulating IL-10-producing B cells in gastric cancer. Exp Cell Res. 2019;384:111652.
Katoh H, Komura D, Konishi H, Suzuki R, Yamamoto A, Kakiuchi M, et al. Immunogenetic profiling for gastric cancers identifies sulfated glycosaminoglycans as major and functional B cell antigens in human malignancies. Cell Rep. 2017;20:1073–87.
Kim J, Cheong JH, Chen J, Hyung WJ, Choi SH, Noh SH. Menetrier’s disease in Korea: report of two cases and review of cases in a gastric cancer prevalent region. Yonsei Med J. 2004;45:555–60.
Lohr M, Edlund K, Botling J, Hammad S, Hellwig B, Othman A, et al. The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 2013;333:222–8.
Matsueda S, Graham DY. Immunotherapy in gastric cancer. World J Gastroenterol. 2014;20:1657–66.
Meshcheryakova A, Tamandl D, Bajna E, Stift J, Mittlboeck M, Svoboda M, et al. B cells and ectopic follicular structures: novel players in anti-tumor programming with prognostic power for patients with metastatic colorectal cancer. PLoS One. 2014;9:e99008.
Nedergaard BS, Ladekarl M, Nyengaard JR, Nielsen K. A comparative study of the cellular immune response in patients with stage IB cervical squamous cell carcinoma. Low numbers of several immune cell subtypes are strongly associated with relapse of disease within 5 years. Gynecol Oncol. 2008;108:106–11.
Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. 2012;18:3281–92.
Nomura A, Grove JS, Stemmermann GN, Severson RK. Cigarette smoking and stomach cancer. Cancer Res. 1990;50:7084.
Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15:160–71.
Sakamoto S, Kagawa S, Kuwada K, Ito A, Kajioka H, Kakiuchi Y, et al. Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer. Oncoimmunology. 2019;8:e1671760.
Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68:5405–13.
Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18:2695–703.
Semper RP, Vieth M, Gerhard M, Mejías-Luque R. Helicobacter pylori exploits the NLRC4 inflammasome to dampen host defenses. J Immunol. 2019;203:2183–93.
Svensson MC, Warfvinge CF, Fristedt R, Hedner C, Borg D, Eberhard J, et al. The integrative clinical impact of tumor-infiltrating T lymphocytes and NK cells in relation to B lymphocyte and plasma cell density in esophageal and gastric adenocarcinoma. Oncotarget. 2017;8:72108–26.
Thrumurthy SG, Chaudry MA, Hochhauser D, Mughal M. The diagnosis and management of gastric cancer. BMJ. 2013;347:f6367.
Tseng CH, Tseng FH. Diabetes and gastric cancer: the potential links. World J Gastroenterol. 2014;20:1701–11.
Yang J, Yan J, Shao J, Xu Q, Meng F, Chen F, et al. Immune-mediated antitumor effect by VEGFR2 selective inhibitor for gastric Cancer. Onco Targets Ther. 2019;12:9757–65.
Yoshida T, Mei H, Dorner T, Hiepe F, Radbruch A, Fillatreau S, et al. Memory B and memory plasma cells. Immunol Rev. 2010;237:117–39.
Zhang H, Yue R, Zhao P, Yu X, Li J, Ma G, et al. Proinflammatory follicular helper T cells promote immunoglobulin G secretion, suppress regulatory B cell development, and correlate with worse clinical outcomes in gastric cancer. Tumour Biol. 2017;39:1010428317705747.
Funding
This study was supported by grants from the National Natural Science Foundation of China (Grant Nos.: 81672707, 31670922, and 81602165), the Key R&D Program of Zhejiang Province (Grant No.: 2020C03029), and the Natural Science Foundation of Zhejiang Province (Grant No.: LY17H160053).
Author information
Authors and Affiliations
Contributions
Z.G.Z., X.Y.X., and J.Z. conceived and designed the experiment; Z.L.N. and D.X. (Dong Xing) collected data and were responsible for data acquisition; T.M.Z., N.D., D.X. (Dan Xiang), J.M.Q., C.Y.H., and X.S. performed the data analysis and statistical analysis; Z.L.N. and D.X. (Dong Xing) wrote the paper and contributed significantly to this work; Z.G.Z., X.Y.X., and J.Z. contributed to the theoretical analysis, they revised the manuscript critically for important intellectual content, and they were co-corresponding authors. All authors gave final approval to the manuscript submission.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethics approval
This study was approved by the Institutional Research Ethics Committee of the Nanfang Hospital, Southern Medical University. Experiments on human tissues were performed in accordance with the Declaration of Helsinki.
Consent to participate
Written informed consent was provided by all subjects.
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.
Rights and permissions
About this article
Cite this article
Ni, Z., Xing, D., Zhang, T. et al. Tumor-infiltrating B cell is associated with the control of progression of gastric cancer. Immunol Res 69, 43–52 (2021). https://doi.org/10.1007/s12026-020-09167-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12026-020-09167-z