To investigate the immunotherapeutic roles and functions of C-C Motif Chemokine Receptor 8 (CCR8) molecule in gastric cancer (GC).
Materials and Methods:
Clinicopathological features of 95 GC cases were collected by a follow-up survey. The expression level of CCR8 was measured by immunohistochemistry (IHC) staining and analyzed with the cancer genome atlas database. The relationship between CCR8 expression and Clinicopathological features of GC cases was evaluated by univariate and multivariate analysis. Flow cytometry was used to determine the expression of cytokines and the proliferation of CD4+ regulator T cells (Tregs) and CD8+ T cells.
Results:
An upregulated expression of CCR8 in GC tissues was associated with tumor grade, nodal metastasis, and overall survival (OS). Tumor-infiltrated Tregs with higher expression of CCR8 produced more IL10 molecules in vitro. In addition, anti-CCR8 blocking downregulated IL10 expression produced by CD4+ Tregs, and reversed the suppression by Tregs on the secretion and proliferation of CD8+ T cells.
Conclusion:
CCR8 molecule could be a prognostic biomarker for GC cases and a therapeutic target for immune treatments.
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References
1.
SungH, FerlayJ, SiegelRL, et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021; 71:209.
2.
LuuXQ, LeeK, JunJK, et al.Effect of gastric cancer screening on long-term survival of gastric cancer patients: Results of Korean national cancer screening program. J Gastroenterol, 2022; 57:464.
AjaniJA, D'AmicoTA, BentremDJ, et al.Gastric Cancer, Version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw, 2022; 20:167.
5.
JoshiSS, BadgwellBD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin, 2021; 71:264.
LordickF, ShitaraK, JanjigianYY. New agents on the horizon in gastric cancer. Ann Oncol, 2017; 28:1767.
8.
RizzoA, MollicaV, RicciAD, et al.Third- and later-line treatment in advanced or metastatic gastric cancer: A systematic review and meta-analysis. Future Oncol, 2020; 16:4409.
9.
ViscardiG, TralongoAC, MassariF, et al.Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: A systematic review and meta-analysis. Eur J Cancer, 2022; 177:175.
10.
HögnerA, MoehlerM. Immunotherapy in gastric cancer. Curr Oncol, 2022; 29:1559.
11.
CameraS, LisciaN, FotiS, et al.Does immunotherapy change the treatment paradigm in metastatic gastric cancer?. Med Oncol (Northwood, London, England), 2022; 39:224.
12.
SmythEC, CervantesA. Addition of nivolumab to chemotherapy in patients with advanced gastric cancer: A relevant step ahead, but still many questions to answer. ESMO Open, 2020; 5:e001107.
13.
RicciAD, RizzoA, Rojas LlimpeFL, et al.Novel HER2-directed treatments in advanced gastric carcinoma: AnotHER Paradigm Shift?. Cancers (Basel), 2021; 13:1664.
14.
KamadaT, TogashiY, TayC, et al.PD-1 regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA, 2019; 116:9999.
15.
RihawiK, RicciAD, RizzoA, et al.Tumor-associated macrophages and inflammatory microenvironment in gastric cancer: Novel translational implications. Int J Mol Sci, 2021; 22:3805.
16.
XiaY, RaoL, YaoH, et al.Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater, 2020; 32:e2002054.
17.
ThompsonED, ZahurakM, MurphyA, et al.Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut, 2017; 66:794.
18.
ZhouC, ZhangJ. Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: Current status and future prospects. Front Med, 2019; 13:12.
19.
WingJB, TanakaA, SakaguchiS. Human FOXP3 regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity, 2019; 50:302.
20.
WangJ, GongR, ZhaoC, et al.Human FOXP3 and tumour microenvironment. Immunology, 2023; 168:248.
21.
TanakaA, SakaguchiS. Regulatory T cells in cancer immunotherapy. Cell Res, 2017; 27:109.
22.
LiuX, ZhangZ, ZhaoG. Recent advances in the study of regulatory T cells in gastric cancer. Int Immunopharmacol, 2019; 73:560.
23.
TanakaA, SakaguchiS. Targeting Treg cells in cancer immunotherapy. Eur J Immunol, 2019; 49:1140.
24.
WhitesideSK, GrantFM, GyoriDS, et al.CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function. Immunology, 2021; 163:512.
25.
BarsheshetY, WildbaumG, LevyE, et al.CCR8FOXp3 T cells as master drivers of immune regulation. Proc Natl Acad Sci USA, 2017; 114:6086.
26.
MoserB. Chemokine receptor-targeted therapies: Special case for CCR8. Cancers, 2022; 14:511.
27.
SebastianiS, AllavenaP, AlbanesiC, et al.Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol (Baltimore, MD: 1950), 2001; 166:996.
28.
D'AmbrosioD, IellemA, BonecchiR, et al.Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J Immunol (Baltimore, MD: 1950). 1998; 161:5111.
29.
ZingoniA, SotoH, HedrickJA, et al.The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells. J Immunol (Baltimore, MD: 1950), 1998; 161:547.
30.
PlitasG, KonopackiC, WuK, et al.Regulatory T cells exhibit distinct features in human breast cancer. Immunity, 2016; 45:1122.
31.
De SimoneM, ArrigoniA, RossettiG, et al.Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity, 2016; 45:1135.
32.
DeesS, GanesanR, SinghS, et al.Regulatory T cell targeting in cancer: Emerging strategies in immunotherapy. Eur J Immunol, 2021; 51:280.
33.
KuroseK, OhueY, WadaH, et al.Phase Ia Study of FoxP3+ CD4 treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. Clin Cancer Res, 2015; 21:4327.
34.
CampbellJR, McDonaldBR, MeskoPB, et al.Fc-Optimized Anti-CCR8 antibody depletes regulatory T cells in human tumor models. Cancer Res, 2021; 81:2983.
35.
KidaniY, NogamiW, YasumizuY, et al.CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory. Proc Natl Acad Sci USA, 2022; 119:e2114282119.
36.
HarunaM, UeyamaA, YamamotoY, et al.The impact of CCR8+ regulatory T cells on cytotoxic T cell function in human lung cancer. Sci Reports, 2022; 12:5377.
37.
SaraivaM, VieiraP, O'GarraA. Biology and therapeutic potential of interleukin-10. J Exp Med, 2020; 217:e20190418.
38.
VillarrealDO, L'HuillierA, ArmingtonS, et al.Targeting CCR8 induces protective antitumor immunity and enhances vaccine-induced responses in colon cancer. Cancer Res, 2018; 78:5340.
39.
Van DammeH, DombrechtB, KissM, et al.Therapeutic depletion of CCR8 tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy. J Immunother Cancer, 2021; 9:e001749.
40.
WangT, ZhouQ, ZengH, et al.CCR8 blockade primes anti-tumor immunity through intratumoral regulatory T cells destabilization in muscle-invasive bladder cancer. Cancer Immunol Immunother, 2020; 69:1855.
41.
KindlundB, Sjöling Å, YakkalaC, et al.CD4 regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-β. Gastric Cancer, 2017; 20:116.
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