The Spatial Distribution of Immune Cell Subpopulations in Hepatocellular Carcinoma

Overview

Journal Cancer Sci

Specialty Oncology

Date 2021 Nov 15

PMID 34779545

Citations 10

Authors

Peng-Cheng Wang

Zhi-Qiang Hu

Shao-Lai Zhou

Song-Yang Yu

Li Mao

Sheng Su

Jia Li

Ning Ren

Xiao-Wu Huang

Affiliations

Soon will be listed here.

Abstract

Infiltrating immune cells in the tumor microenvironment (TME) influence tumor progression and patient prognosis, making them attractive therapeutic targets for immunotherapy research. A deeper understanding of immune cell distributions in the TME in hepatocellular carcinoma (HCC) is needed to identify interactions among different immune cell types that might impact the effectiveness of potential immunotherapies. We performed multiplex immunohistochemistry using a tissue microarray of samples from 302 patients with HCC to elucidate the spatial distributions of immune cell subpopulations (CD3 , CD4 , CD8 , CD66b , and CD68 ) in HCC and normal liver tissues. We analyzed the associations between different immune subpopulations using Pearson's correlation. G(r) functions, K(r) functions and Euclidean distance were applied to characterize the bivariate distribution patterns among the immune cell types. Cox regression and Kaplan-Meier analysis were used to evaluate the associations between tumor infiltration by different immune cells and patient outcomes after curative surgery. We also analyzed the relationship between the spatial distribution of different immune cell subpopulations with HCC patient prognosis. We found that the immune cell spatial distribution in the HCC TME is heterogeneous. Our study provides a theoretical basis for HCC immunotherapy.

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References

de Martel C, Maucort-Boulch D, Plummer M, Franceschi S . World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology. 2015; 62(4):1190-200. PMC: 5019261. DOI: 10.1002/hep.27969. View

Zhou S, Yin D, Hu Z, Luo C, Zhou Z, Xin H . A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression. Hepatology. 2019; 70(4):1214-1230. DOI: 10.1002/hep.30630. View

Zhou Z, Wang P, Sun R, Li J, Hu Z, Xin H . Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3. J Immunother Cancer. 2021; 9(3). PMC: 7949476. DOI: 10.1136/jitc-2020-001946. View

Quail D, Joyce J . Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19(11):1423-37. PMC: 3954707. DOI: 10.1038/nm.3394. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

Powell D, Huttenlocher A . Neutrophils in the Tumor Microenvironment. Trends Immunol. 2015; 37(1):41-52. PMC: 4707100. DOI: 10.1016/j.it.2015.11.008. View

Maman S, Witz I . A history of exploring cancer in context. Nat Rev Cancer. 2018; 18(6):359-376. DOI: 10.1038/s41568-018-0006-7. View

Zhou Z, Dai Z, Zhou S, Hu Z, Chen Q, Zhao Y . HNRNPAB induces epithelial-mesenchymal transition and promotes metastasis of hepatocellular carcinoma by transcriptionally activating SNAIL. Cancer Res. 2014; 74(10):2750-62. DOI: 10.1158/0008-5472.CAN-13-2509. View

Prestipino A, Zeiser R . Clinical implications of tumor-intrinsic mechanisms regulating PD-L1. Sci Transl Med. 2019; 11(478). DOI: 10.1126/scitranslmed.aav4810. View

10.

Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, de Moura M . Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology. 2017; 153(3):812-826. DOI: 10.1053/j.gastro.2017.06.007. View

11.

Mikucki M, Fisher D, Matsuzaki J, Skitzki J, Gaulin N, Muhitch J . Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015; 6:7458. PMC: 4605273. DOI: 10.1038/ncomms8458. View

12.

Governa V, Trella E, Mele V, Tornillo L, Amicarella F, Cremonesi E . The Interplay Between Neutrophils and CD8 T Cells Improves Survival in Human Colorectal Cancer. Clin Cancer Res. 2017; 23(14):3847-3858. DOI: 10.1158/1078-0432.CCR-16-2047. View

13.

Liu P, Zhao L, Pol J, Levesque S, Petrazzuolo A, Pfirschke C . Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat Commun. 2019; 10(1):1486. PMC: 6445096. DOI: 10.1038/s41467-019-09415-3. View

14.

de Oca R, Buendia A, Del Rio L, Sanchez J, Salinas J, Navarro J . Polymorphonuclear neutrophils are necessary for the recruitment of CD8(+) T cells in the liver in a pregnant mouse model of Chlamydophila abortus (Chlamydia psittaci serotype 1) infection. Infect Immun. 2000; 68(3):1746-51. PMC: 97343. DOI: 10.1128/IAI.68.3.1746-1751.2000. View

15.

Gao Q, Zhou J, Wang X, Qiu S, Song K, Huang X . Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol. 2011; 19(2):455-66. DOI: 10.1245/s10434-011-1864-3. View

16.

Carstens J, Correa de Sampaio P, Yang D, Barua S, Wang H, Rao A . Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Commun. 2017; 8:15095. PMC: 5414182. DOI: 10.1038/ncomms15095. View

17.

Singel K, Segal B . Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal. Immunol Rev. 2016; 273(1):329-43. PMC: 5477672. DOI: 10.1111/imr.12459. View

18.

Zamarron B, Chen W . Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011; 7(5):651-8. PMC: 3107473. DOI: 10.7150/ijbs.7.651. View

19.

Lim K, Hyun Y, Lambert-Emo K, Capece T, Bae S, Miller R . Neutrophil trails guide influenza-specific CD8⁺ T cells in the airways. Science. 2015; 349(6252):aaa4352. PMC: 4809646. DOI: 10.1126/science.aaa4352. View

20.

Ringelhan M, Pfister D, OConnor T, Pikarsky E, Heikenwalder M . The immunology of hepatocellular carcinoma. Nat Immunol. 2018; 19(3):222-232. DOI: 10.1038/s41590-018-0044-z. View