Top

Gastric Cancer

Published in:

01-03-2021 | Gastric Cancer | Original Article

Expression of the immune checkpoint molecule V-set immunoglobulin domain-containing 4 is associated with poor prognosis in patients with advanced gastric cancer

Authors: So-Woon Kim, Jin Roh, Hye Seung Lee, Min-Hee Ryu, Young-Soo Park, Chan-Sik Park

Published in: Gastric Cancer | Issue 2/2021

Abstract

Background

Recent clinical studies on immune checkpoint (IC) inhibitors in the context of advanced gastric cancer (AGC) have failed to show significant survival benefits but have suggested the possible role of IC inhibitors in anti-AGC immunity. Considering the low efficacy of targeted drugs in AGC, there is an urgent need for the discovery of new targets for the development of immunotherapeutics and prognostic markers for patient selection. This study aimed to investigate the expression of a new IC molecule, V-set Ig domain-containing 4 (VSIG4), and its clinical significance in AGC and other major cancers.

Methods

We analyzed the expression of VSIG4 and its correlation with survival in various carcinomas, including 882 surgically resected samples from patients with stage II–III AGC (two academic hospitals).

Results

VSIG4 positivity in AGC was significantly associated with overall survival (OS; Hazard ratio (HR) = 2.661, 95% confidence interval [CI] = 2.012–3.519, P < 0.001) and event-free survival (HR = 2.8, 95% CI = 2.18–3.72, P < 0.001). These findings were successfully validated in independent cohorts. VSIG4 expression was also significantly correlated with low intratumoral CD8 + T-cell infiltration (CD8i) (P = 0.029) and high Foxp3 + /CD8i ratio (P = 0.026), which is consistent with the previously reported immunological function of VSIG4. However, VSIG4 expression was not associated with survival in other cancers (colon, P = 0.459; lung, P = 0.275; kidney, P = 0.121; breast, P = 0.147).

Conclusion

Our results suggest that VSIG4 is an independent prognostic factor in AGC and also implies that VSIG4 is a second-tier IC molecule in AGC, thus, providing an important basis for the development of gastric cancer-specific immunotherapeutics.

Available only for authorised users

Shitara K, Ozguroglu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392:123–33. https://doi.org/10.1016/S0140-6736(18)31257-1.CrossRefPubMed

Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4:e180013. https://doi.org/10.1001/jamaoncol.2018.0013.CrossRefPubMedPubMedCentral

Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97. https://doi.org/10.1016/S0140-6736(10)61121-X.CrossRefPubMed

Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34:1448–544. https://doi.org/10.1200/JCO.2015.63.5995.CrossRefPubMed

Johnson DB, Frampton GM, Rioth MJ, et al. Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res. 2016;4:959–67. https://doi.org/10.1158/2326-6066.CIR-16-0143.CrossRefPubMedPubMedCentral

Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71. https://doi.org/10.1016/S0140-6736(17)31827-5.CrossRefPubMed

Salati M, Di Emidio K, Tarantino V, et al. Second-line treatments: moving towards an opportunity to improve survival in advanced gastric cancer? ESMO Open. 2017;2:e000206. https://doi.org/10.1136/esmoopen-2017-000206.CrossRefPubMedPubMedCentral

Peeters M, Cervantes A, Moreno Vera S, et al. Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers. Future Oncol. 2018;14:1629–45. https://doi.org/10.2217/fon-2018-0147.CrossRefPubMed

Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9. https://doi.org/10.1016/S0140-6736(13)61719-5.CrossRefPubMed

10.

Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–355. https://doi.org/10.1016/S1470-2045(14)70420-6.CrossRefPubMed

11.

Gide TN, Quek C, Menzies AM, et al. Distinct immune cell populations define response to anti-PD-1 monotherapy and anti-PD-1/anti-CTLA-4 combined therapy. Cancer Cell. 2019;35(238–55):e6. https://doi.org/10.1016/j.ccell.2019.01.003.CrossRef

12.

Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44:989–1004. https://doi.org/10.1016/j.immuni.2016.05.001.CrossRefPubMedPubMedCentral

13.

Shen P, Yue R, Tang J, et al. Preferential Tim-3 expression on Treg and CD8(+) T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer. Am J Transl Res. 2016;8:3419–28.PubMedPubMedCentral

14.

Liao Y, Guo S, Chen Y, et al. VSIG4 expression on macrophages facilitates lung cancer development. Lab Invest. 2014;94:706–15. https://doi.org/10.1038/labinvest.2014.73.CrossRefPubMed

15.

Yuan X, Yang BH, Dong Y, et al. CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells. eLife. 2017. https://doi.org/10.7554/eLife.29540.CrossRefPubMedPubMedCentral

16.

Vogt L, Schmitz N, Kurrer MO, et al. VSIG4, a B7 family-related protein, is a negative regulator of T cell activation. J Clin Invest. 2006;116:2817–26. https://doi.org/10.1172/JCI25673.CrossRefPubMedPubMedCentral

17.

Li J, Diao B, Guo S, et al. VSIG4 inhibits proinflammatory macrophage activation by reprogramming mitochondrial pyruvate metabolism. Nat Commun. 2017;8:1322. https://doi.org/10.1038/s41467-017-01327-4.CrossRefPubMedPubMedCentral

18.

Xu T, Jiang Y, Yan Y, et al. VSIG4 is highly expressed and correlated with poor prognosis of high-grade glioma patients. Am J Transl Res. 2015;7:1172–80.PubMedPubMedCentral

19.

Roh J, Jeon Y, Lee AN, et al. The immune checkpoint molecule V-set Ig domain-containing 4 is an independent prognostic factor for multiple myeloma. Oncotarget. 2017;8:58122–32. https://doi.org/10.18632/oncotarget.19468.CrossRefPubMedPubMedCentral

20.

Amin MB, Edge SB, Greene FL. AJCC cancer staging manual. 8th ed. Chicago: Springer; 2017.CrossRef

21.

Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:3798–807. https://doi.org/10.1200/JCO.2003.11.069.CrossRefPubMed

22.

Budczies J, Klauschen F, Sinn BV, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7:e51862. https://doi.org/10.1371/journal.pone.0051862.CrossRefPubMedPubMedCentral

23.

Boger C, Behrens HM, Mathiak M, et al. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget. 2016;7:24269–83. https://doi.org/10.18632/oncotarget.8169.CrossRefPubMedPubMedCentral

24.

Kim JY, Kim WG, Kwon CH, et al. Differences in immune contextures among different molecular subtypes of gastric cancer and their prognostic impact. Gastric Cancer. 2019;22:1164–75. https://doi.org/10.1007/s10120-019-00974-4.CrossRefPubMed

25.

Carpenter AE, Jones TR, Lamprecht MR, et al. Cell Profiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 2006;7:R100. https://doi.org/10.1186/gb-2006-7-10-r100.CrossRefPubMedPubMedCentral

26.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9. https://doi.org/10.1038/nature13480.CrossRef

27.

Nagai H, Muto M. Optimal management of immune-related adverse events resulting from treatment with immune checkpoint inhibitors: a review and update. Int J Clin Oncol. 2018;23:410–20. https://doi.org/10.1007/s10147-018-1259-6.CrossRefPubMed

28.

Ropponen KM, Eskelinen MJ, Lipponen PK, et al. Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol. 1997;182:318–24. https://doi.org/10.1002/(SICI)1096-9896(199707)182:3<318:AID-PATH862>3.0.CO;2-6.CrossRefPubMed

29.

Lipponen PK, Eskelinen MJ, Jauhiainen K, et al. Tumour infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer. Eur J Cancer. 1992;29A:69–75. https://doi.org/10.1016/0959-8049(93)90579-5.CrossRefPubMed

30.

Karja V, Aaltomaa S, Lipponen P, et al. Tumour-infiltrating lymphocytes: a prognostic factor of PSA-free survival in patients with local prostate carcinoma treated by radical prostatectomy. Anticancer Res. 2005;25:4435–8.PubMed

31.

Fridman WH, Pages F, Sautes-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306. https://doi.org/10.1038/nrc3245.CrossRefPubMed

32.

Jung K, Kang M, Park C, et al. Protective role of V-set and immunoglobulin domain-containing 4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and natural killer T-cells. Hepatology. 2012;56:1838–48. https://doi.org/10.1002/hep.25906.CrossRefPubMed

33.

Tran PN, Sarkissian S, Chao J, et al. PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence. Gastrointest Cancer. 2017;7:1–11. https://doi.org/10.2147/GICTT.S113525.CrossRefPubMedPubMedCentral

34.

Chen C, Zhang F, Zhou N, et al. Efficacy and safety of immune checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic review and meta-analysis. Oncoimmunology. 2019;8:e1581547. https://doi.org/10.1080/2162402X.2019.1581547.CrossRefPubMedPubMedCentral

35.

Cui J, Yin Y, Ma Q, et al. Comprehensive characterization of the genomic alterations in human gastric cancer. Int J Cancer. 2015;137:86–95. https://doi.org/10.1002/ijc.29352.CrossRefPubMed

36.

Charalampakis N, Economopoulou P, Kotsantis I, et al. Medical management of gastric cancer: a 2017 update. Cancer Med. 2018;7:123–33. https://doi.org/10.1002/cam4.1274.CrossRefPubMed

37.

Liu X, Meltzer SJ. Gastric cancer in the era of precision medicine. Cell Mol Gastroenterol Hepatol. 2017;3:348–58. https://doi.org/10.1016/j.jcmgh.2017.02.003.CrossRefPubMedPubMedCentral

38.

Marshall HT, Djamgoz MBA. Immuno-oncology: emerging targets and combination therapies. Front Oncol. 2018;8:315. https://doi.org/10.3389/fonc.2018.00315.CrossRefPubMedPubMedCentral

39.

Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol. 2014;25:1032–8. https://doi.org/10.1093/annonc/mdu100.CrossRefPubMedPubMedCentral

Title: Expression of the immune checkpoint molecule V-set immunoglobulin domain-containing 4 is associated with poor prognosis in patients with advanced gastric cancer
Authors: So-Woon Kim
Jin Roh
Hye Seung Lee
Min-Hee Ryu
Young-Soo Park
Chan-Sik Park
Publication date: 01-03-2021
Publisher: Springer Singapore
Keywords: Gastric Cancer
Gastric Cancer
Published in: Gastric Cancer / Issue 2/2021
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI: https://doi.org/10.1007/s10120-020-01120-1

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Expression of the immune checkpoint molecule V-set immunoglobulin domain-containing 4 is associated with poor prognosis in patients with advanced gastric cancer

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2021

Gastric equivalent of the ‘Holy Plane’ to standardize the surgical concept of stomach cancer to mesogastric excision: updating Jamieson and Dobson’s historic schema

Molecular alterations in gastric cancer and the surrounding intestinal metaplastic mucosa: an analysis of isolated glands

Docetaxel plus S-1 versus cisplatin plus S-1 in unresectable gastric cancer without measurable lesions: a randomized phase II trial (HERBIS-3)

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis

Promising aberrant DNA methylation marker to predict gastric cancer development in individuals with family history and long-term effects of H. pylori eradication on DNA methylation

Prognostic significance of sarcopenia in microsatellite-stable gastric cancer patients treated with programmed death-1 inhibitors

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page