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SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function

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Abstract

Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Robert C, Robert C (2020) A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 11(1):3801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    Article  CAS  PubMed  Google Scholar 

  3. Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319

    Article  PubMed  Google Scholar 

  4. Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim ST, Cristescu R, Bass AJ et al (2018) Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 24(9):1449–1458

    Article  CAS  PubMed  Google Scholar 

  6. Kang YK, Boku N, Satoh T et al (2017) 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 390(10111):2461–2471

    Article  CAS  PubMed  Google Scholar 

  7. Janjigian YY et al (2021) First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398:27–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78

    Article  CAS  PubMed  Google Scholar 

  9. Doedens AL, Stockmann C, Rubinstein MP et al (2010) Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 70(19):7465–7475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin C, He H, Liu H et al (2019) Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut 68(10):1764–1773

    Article  CAS  PubMed  Google Scholar 

  11. Menguy S, Prochazkova-Carlotti M, Beylot-Barry M et al (2018) PD-L1 and PD-L2 are differentially expressed by macrophages or tumor cells in primary cutaneous diffuse large B-cell lymphoma. Leg Type Am J Surg Pathol 42(3):326–334

    Article  PubMed  Google Scholar 

  12. Wang XB, Giscombe R, Yan Z, Heiden T, Xu D, Lefvert AK (2002) Expression of CTLA-4 by human monocytes. Scand J Immunol 55(1):53–60 

    Article  CAS  PubMed  Google Scholar 

  13. Kryczek I, Zou L, Rodriguez P et al (2006) B7–H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203(4):871–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Munday J, Kerr S, Ni J et al (2001) Identification, characterization and leucocyte expression of SIGLEC-10, a novel human sialic acid-binding receptor. Biochem J 355(Pt 2):489–497 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yin SS, Gao FH (2020) Molecular Mechanism of Tumor Cell Immune Escape Mediated by CD24/SIGLEC-10. Front Immunol 11:1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bandala-Sanchez E, G Bediaga N, Goddard-Borger ED et al (2018) CD52 glycan binds the proinflammatory B box of HMGB1 to engage the SIGLEC-10 receptor and suppress human T cell function. Proc Natl Acad Sci U S A 115(30):7783–7788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barkal AA, Brewer RE, Markovic M et al (2019) CD24 signalling through macrophage SIGLEC-10 is a target for cancer immunotherapy. Nature 572(7769):392–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang J, Sun J, Liu LN et al (2019) SIGLEC-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med 25(4):656–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang KY, Qi LL, Kang FB, Wang L (2022) The intriguing roles of SIGLEC family members in the tumor microenvironment. Biomark Res 10(1):22

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209

    Article  Google Scholar 

  21. Kumar V, Ramnarayanan K, Sundar R et al (2022) Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer. Cancer Discov 12(3):670–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Satija R, Farrell JA, Gennert D, Schier AF, Regev A (2015) Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 33(5):495–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stuart T, Butler A, Hoffman P et al (2019) Comprehensive integration of single-cell data. Cell 177(7):1888-1902.e21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim EH, Sullivan JA, Plisch EH et al (2012) Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J Immunol 188(9):4305–4314

    Article  CAS  PubMed  Google Scholar 

  25. D’Souza WN, Chang CF, Fischer AM, Li M, Hedrick SM (2008) The Erk2 MAPK regulates CD8 T cell proliferation and survival. J Immunol 181(11):7617–7629

    Article  PubMed  Google Scholar 

  26. Rincón M, Pedraza-Alva G (2003) JNK and p38 MAP kinases in CD4+ and CD8+ T cells[J]. Immunol Rev 192(1):131–142

    Article  PubMed  Google Scholar 

  27. Adeegbe DO, Liu Y, Lizotte PH et al (2017) Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non-small cell lung cancer. Cancer Discov 7(8):852–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fraschilla I, Pillai S (2017) Viewing SIGLECs through the lens of tumor immunology. Immunol Rev 276(1):178–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stoger JL, Goossens P, de Winther MPJ (2010) Macrophage heterogeneity: relevance and functional implications in atherosclerosis. Curr Vasc Pharmacol 8(2):233–248

    Article  PubMed  Google Scholar 

  30. Petty AJ, Yang Y (2017) Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy 9(3):289–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kersten K, Hu KH, Combes AJ et al (2022) Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer. Cancer Cell 40(6):624-638.e9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li B, Zhang B, Wang X et al (2020) Expression signature, prognosis value, and immune characteristics of SIGLEC-15 identified by pan-cancer analysis[J]. Oncoimmunology 9(1):1807291

    Article  PubMed  PubMed Central  Google Scholar 

  33. Stasi R (2008) Gemtuzumab ozogamicin: an anti-CD33 immunoconjugate for the treatment of acute myeloid leukaemia. Expert Opin Biol Ther 8(4):527–540

    Article  CAS  PubMed  Google Scholar 

  34. Adeel K, Fergusson NJ, Shorr R, Atkins H, Hay KA (2021) Efficacy and safety of CD22 chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies: a protocol for a systematic review and meta-analysis. Syst Rev 10(1):35

    Article  PubMed  PubMed Central  Google Scholar 

  35. Xiao N, Zhu X, Li K et al (2021) Blocking SIGLEC-10hi tumor-associated macrophages improves anti-tumor immunity and enhances immunotherapy for hepatocellular carcinoma. Exp Hematol Oncol 10(1):36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank National Natural Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China, and National Key Research and Development Program of China for their financial support.

Funding

Funding was provided by National Natural Science Foundation of China, (Grant Nos. 32070878, 81970497).

Author information

Author notes

  1. Yixian Guo, Shouyu Ke and Feng Xie are co-first authors.

Authors and Affiliations

  1. GI Division, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China

    Yixian Guo & Hong Lu

  2. Department of Gastrointestinal Surgery, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China

    Shouyu Ke, Xu Liu, Zeyu Wang, Danhua Xu, Gang Zhao & Wenyi Zhao

  3. School of Medicine, Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, 200025, China

    Feng Xie & Jieqiong Chen

  4. Department of Immunology and Microbiology, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Feng Xie & Jieqiong Chen

  5. Department of Pathology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China

    Yanying Shen

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  1. Yixian Guo
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Contributions

All authors contributed to the study conception and design. Experiment was designed and performed by YG and SK. Data collection and analysis were performed by FX and YG. Manuscript was written by YG, SK, and JC. Pathological analysis was performed by YS and XL. Bioinformatics analysis was performed by FX and DX. The manuscript was revised by JC. The study was designed and supervised by GZ, HL, and WZ. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Wenyi Zhao or Hong Lu.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

All experiments were approved by the Ethical Committee of the Shanghai Jiao Tong University School of Medicine, Renji Hospital (no. 2017–114-CR-02). All procedures followed the ethical guidelines of the Declaration of Helsinki and the guidelines of the China Ethics Review Committee before starting the experiment. Informed consent or a substitute for it was obtained from all patients included in this study.

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Gating strategy (TIF 2462 KB)

A

CD163 and CD206 expression in SIGLEC10+ macrophage and SIGLEC10- macrophage were measured by FACS. B TIGIT, TNFRSF1B, CD44 and ICOS expression of CD8+ T cell in tumor tissue and normal tissue from gastric cancer subjects were measured by FACS. C TNF, SPP1 and NECTIN2 expression of SIGLEC10+ macrophage in tumor tissue and normal tissue from gastric cancer subjects were measured by FACS (TIF 2005 KB)

A

SIGLEC10 expression in SIGLEC10/Ctrl-overexpression (SIGLEC10/Ctrl-OE) macrophage were measured by FACS. B CD8+ T cells were isolated by magnetic beads from GC patients’ samples. Celltrace Violet (CTV) labeled CD8+ T cell macrophage were co-culture with SIGLEC10/Ctrl-OE macrophage for 72 hrs at ratios (1:2), then the proliferate ability of CD8+ T cells was measured by FACS. C CD8+ T cells were isolated by magnetic beads from GC patients’ samples. CD8+ T cells were co-culture with SIGLEC10/Ctrl-OE macrophage for 72 hrs at ratio (macrophages:CD8+ T cells, 1:2), then the TNF-α and IFN-γ expression of CD8+ T cells was measured by FACS (TIF 1582 KB)

A

NSG mice were entailed injection with tumor-matched PBMC (5×106). Then patients-derived tumor was implanted 2 days after PBMC engraftment. Mice received anti-SIGLEC10 mAb or IgG isotype control treatment 6 days after tumor engraftment. B Tumor volumes were measured every 2 days. The plot showed the tumor growth curve. C Tumor volumes on day 24. D The SIGLEC10 expression of tumor-infiltrating macrophage in different groups was measured by FACS. E&F The TNF-α and IFN-γ expression of tumor-infiltrating CD8+ T cells in different groups were measured by FACS (TIF 1919 KB)

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Guo, Y., Ke, S., Xie, F. et al. SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function. Cancer Immunol Immunother 72, 3229–3242 (2023). https://doi.org/10.1007/s00262-023-03488-2

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