Abstract
Purpose
Defining the phenotypic characteristics of CD8+ T cell subsets in gastric cancer (GC) can help remodel the immune microenvironment of the tumor, thereby improving patient prognosis. CD226 has recently been shown to regulate the activity of CD8+ T cell in several malignancies. However, the clinical relevance of CD226+CD8+ T cells in GC remains unclear.
Methods
Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 316), The Cancer Genome Atlas (TCGA) cohort (n = 407), KUGH/KUCM cohort (n = 202), and Asian Cancer Research Group (ACRG) cohort (n = 300) were included in prognosis and response to adjuvant chemotherapy (ACT) analyses. Flow cytometry and multiplex immunostaining were used to characterize CD226+CD8+ T cells.
Results
CD226+CD8+ T cells predicted favorable outcomes in patients undergoing curative resection for GC. GC patients with high CD226+CD8+ T cell infiltration benefitted more from adjuvant chemotherapy. CD155 is upregulated in GC tissues and is associated with decreased intra-tumoral CD226+CD8+ T cell infiltration. The combination of intra-tumoral CD226+CD8+ T cells and CD155 is a strong prognostic predictor in patients with GC.
Conclusion
CD226+CD8+ T cells may represent a novel therapeutic target and a useful marker of prognosis and therapeutic response in patients with GC.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ACT:
-
Adjuvant chemotherapy
- GC:
-
Gastric cancer
- mIHF:
-
Multiple immunofluorescence
References
Braun M, Aguilera AR, Sundarrajan A et al (2020) CD155 on Tumor cells drives resistance to immunotherapy by inducing the degradation of the activating receptor CD226 in CD8(+) T cells. Immunity 53:805–823. https://doi.org/10.1016/j.immuni.2020.09.010
Danisch S, Qiu Q, Seth S et al (2013) (2012) CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer’s Patches. Immunobiology 218:152–158. https://doi.org/10.1016/j.imbio.02.010
Gaud G, Roncagalli R, Chaoui K et al (2018) The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4(+) T cells. Sci Signal. https://doi.org/10.1126/scisignal.aar3083
Gilfillan S, Chan CJ, Cella M et al (2008) DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J Exp Med 205:2965–2973. https://doi.org/10.1084/jem.20081752
Han J, Khatwani N, Searles TG et al (2020) Memory CD8(+) T cell responses to cancer. Semin Immunol 49:101435. https://doi.org/10.1016/j.smim.2020.101435
Hirota T, Irie K, Okamoto R et al (2005) Transcriptional activation of the mouse Necl-5/Tage4/PVR/CD155 gene by fibroblast growth factor or oncogenic Ras through the Raf-MEK-ERK-AP-1 pathway. Oncogene 24:2229–2235. https://doi.org/10.1038/sj.onc.1208409
Koyama M, Kuns RD, Olver SD et al (2013) Promoting regulation via the inhibition of DNAM-1 after transplantation. Blood 121:3511–3520. https://doi.org/10.1182/blood-2012-07-444026
Lees JR (2020) CD8+ T cells: The past and future of immune regulation. Cell Immunol 357:104212. https://doi.org/10.1016/j.cellimm.2020.104212
Niederlova V, Tsyklauri O, Chadimova T et al (2021) CD8(+) Tregs revisited: a heterogeneous population with different phenotypes and properties. Eur J Immunol 51:512–530. https://doi.org/10.1002/eji.202048614
O’Donnell JS, Madore J, Li XY et al (2020) Tumor intrinsic and extrinsic immune functions of CD155. Semin Cancer Biol 65:189–196. https://doi.org/10.1016/j.semcancer.2019.11.013
Shibuya A, Campbell D, Hannum C et al (1996) DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4:573–581. https://doi.org/10.1016/s1074-7613(00)70060-4
Stamm H, Wellbrock J, Fiedler W (2018) Interaction of PVR/PVRL2 with TIGIT/DNAM-1 as a novel immune checkpoint axis and therapeutic target in cancer. Mamm Genome 29:694–702. https://doi.org/10.1007/s00335-018-9770-7
Tsuburaya A, Guan J, Yoshida K et al (2021) Clinical biomarkers in adjuvant chemotherapy for gastric cancer after D2 dissection by a pooled analysis of individual patient data from large randomized controlled trials. Gastric Cancer 24:1184–1193. https://doi.org/10.1007/s10120-021-01228-y
Weulersse M, Asrir A, Pichler AC et al (2020) Eomes-dependent loss of the Co-activating receptor CD226 restrains CD8(+) T cell anti-tumor functions and limits the efficacy of cancer immunotherapy. Immunity 53:824–839. https://doi.org/10.1016/j.immuni.2020.09.006
Yamashita K, Hosoda K, Niihara M et al (2021) History and emerging trends in chemotherapy for gastric cancer. Ann Gastroenterol Surg 5:446–456. https://doi.org/10.1002/ags3.12439
Acknowledgements
We thank Dr. Zhen Xiang and Dr. Siyuan Liang for their helpful discussion and technical assistance.
Funding
National Natural Science Foundation of China (81902392); Clinical Research Plan of SHDC (No. SHDC2020CR3033B).
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YZ: performed the experiments; YZ: analyzed the data and prepared the manuscript; YZ, ZZ, JG and HH: provided the samples. YZ and HH: wrote the paper; YZ, ZZ, JG, YH and HH: commented on the study and revised the paper; HH: supervised the project.
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Zhang, Y., Zhao, Zx., Gao, Jp. et al. Tumor-infiltrating CD226+CD8+ T cells are associated with postoperative prognosis and adjuvant chemotherapeutic benefits in gastric cancer patients. J Cancer Res Clin Oncol 149, 4381–4389 (2023). https://doi.org/10.1007/s00432-022-04346-x
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DOI: https://doi.org/10.1007/s00432-022-04346-x