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Journal of Translational Medicine

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Open Access 01-12-2022 | Metastasis | Research

Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases

Authors: Yangsong He, Yanan Han, A-hui Fan, Danxiu Li, Boda Wang, Kun Ji, Xin Wang, Xiaodi Zhao, Yuanyuan Lu

Published in: Journal of Translational Medicine | Issue 1/2022

Abstract

Background

Liver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor.

Methods

Tissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (< 150 µm from the tumor center, TF) and peritumoral region (≥ 150 µm from the tumor center, PT) was evaluated via comparison. The expression of CD68 and CD163 in different regions was further analyzed based on the cell colocalization method. In addition, different immune phenotypes were studied and compared according to the degree of CD8 infiltration.

Results

The expression trends of 12 markers in the TF and TC regions were basically the same in the primary tumor and liver metastasis lesions. However, in comparison of the TF and PT regions, the expression trends were not identical between primary and liver metastases, especially CD163, which was more highly expressed in the PT region relative to the TF region. In the contrast of different space distribution, the expression of CD163 was higher in liver metastases than in the primary foci. Further analysis of CD68 and CD163 via colocalization revealed that the distribution of macrophages in liver metastases was significantly different from that in the primary foci, with CD68⁻CD163⁺ macrophages predominating in liver metastases. In addition, among the three immunophenotypes, CD163 expression was highest in the immune rejection phenotype.

Conclusions

The immune cells found in the primary tumors of colorectal cancer differed from those in liver metastases in terms of their spatial distribution. More immunosuppressive cells were present in the liver metastases, with the most pronounced differential distribution found for macrophages. CD68⁻CD163⁺ macrophages may be associated with intrahepatic immunosuppression and weak immunotherapeutic effects.

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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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(3):209–49. https://doi.org/10.3322/caac.21660.CrossRefPubMed

Shi JF, Wang L, Ran JC, Wang H, Liu CC, Zhang HZ, et al. Clinical characteristics, medical service utilization, and expenditure for colorectal cancer in China, 2005 to 2014: overall design and results from a multicenter retrospective epidemiologic survey. Cancer. 2021;127(11):1880–93. https://doi.org/10.1002/cncr.33445.CrossRefPubMed

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, Group EGW. Metastatic colorectal cancer: esmo clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii1-9. https://doi.org/10.1093/annonc/mdu260.CrossRefPubMed

Xu J, Fan J, Qin X, Cai J, Gu J, Wang S, et al. Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (Version 2018). J Cancer Res Clin Oncol. 2018;145(3):725–36. https://doi.org/10.1007/s00432-018-2795-1.CrossRefPubMed

Sahin IH, Akce M, Alese O, Shaib W, Lesinski GB, El-Rayes B, et al. Immune checkpoint inhibitors for the treatment of Msi-H/Mmr-D colorectal cancer and a perspective on resistance mechanisms. Br J Cancer. 2019;121(10):809–18. https://doi.org/10.1038/s41416-019-0599-y.CrossRefPubMedPubMedCentral

Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18. https://doi.org/10.1056/NEJMoa2017699.CrossRefPubMed

Lindblad KE, Lujambio A. Liver metastases inhibit immunotherapy efficacy. Nat Med. 2021;27(1):25–7. https://doi.org/10.1038/s41591-020-01190-9.CrossRefPubMed

Dagenborg VJ, Marshall SE, Yaqub S, Grzyb K, Boye K, Lund-Iversen M, et al. Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases. Cancer Biol Ther. 2020;21(5):432–40. https://doi.org/10.1080/15384047.2020.1721252.CrossRefPubMedPubMedCentral

Ye L, Zhang T, Kang Z, Guo G, Sun Y, Lin K, et al. Tumor-infiltrating immune cells act as a marker for prognosis in colorectal cancer. Front Immunol. 2019;10:2368. https://doi.org/10.3389/fimmu.2019.02368.CrossRefPubMedPubMedCentral

10.

Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179. https://doi.org/10.1038/srep15179.CrossRefPubMedPubMedCentral

11.

Kim J, Kwon J, Kim M, Do J, Lee D, Han H. Low-dielectric-constant polyimide aerogel composite films with low water uptake. Polym J. 2016;48(7):829–34. https://doi.org/10.1038/pj.2016.37.CrossRef

12.

Inagaki K, Kunisho S, Takigawa H, Yuge R, Oka S, Tanaka S, et al. Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression. Cancer Sci. 2021;112(7):2692–704. https://doi.org/10.1111/cas.14940.CrossRefPubMedPubMedCentral

13.

Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13(5):1472–9. https://doi.org/10.1158/1078-0432.Ccr-06-2073.CrossRefPubMed

14.

Yang C, Wei C, Wang S, Shi D, Zhang C, Lin X, et al. Elevated Cd163(+)/Cd68(+) ratio at tumor invasive front is closely associated with aggressive phenotype and poor prognosis in colorectal cancer. Int J Biol Sci. 2019;15(5):984–98. https://doi.org/10.7150/ijbs.29836.CrossRefPubMedPubMedCentral

15.

Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549–55. https://doi.org/10.1038/s41586-019-1922-8.CrossRefPubMedPubMedCentral

16.

Horzum U, Yoyen-Ermis D, Taskiran EZ, Yilmaz KB, Hamaloglu E, Karakoc D, et al. Cd66b(+) monocytes represent a proinflammatory myeloid subpopulation in cancer. Cancer Immunol Immunother. 2021;70(1):75–87. https://doi.org/10.1007/s00262-020-02656-y.CrossRefPubMed

17.

Bottcher JP, Reis e Sousa C. The role of type 1 conventional dendritic cells in cancer immunity. Trends Cancer. 2018;4(11):784–92. https://doi.org/10.1016/j.trecan.2018.09.001.CrossRefPubMedPubMedCentral

18.

Terren I, Orrantia A, Vitalle J, Zenarruzabeitia O, Borrego F. Nk cell metabolism and tumor microenvironment. Front Immunol. 2019;10:2278. https://doi.org/10.3389/fimmu.2019.02278.CrossRefPubMedPubMedCentral

19.

Yaghoubi N, Soltani A, Ghazvini K, Hassanian SM, Hashemy SI. Pd-1/ Pd-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother. 2019;110:312–8. https://doi.org/10.1016/j.biopha.2018.11.105.CrossRefPubMed

20.

Dai G, Ding K, Cao Q, Xu T, He F, Liu S, et al. Emodin suppresses growth and invasion of colorectal cancer cells by inhibiting Vegfr2. Eur J Pharmacol. 2019;859:172525. https://doi.org/10.1016/j.ejphar.2019.172525.CrossRefPubMed

21.

Ni L, Lu J. Interferon gamma in cancer immunotherapy. Cancer Med. 2018;7(9):4509–16. https://doi.org/10.1002/cam4.1700.CrossRefPubMedPubMedCentral

22.

Li P, Xiao ZT, Braciak TA, Ou QJ, Chen G, Oduncu FS. Association between Ki67 index and clinicopathological features in colorectal cancer. Oncol Res Treat. 2016;39(11):696–702. https://doi.org/10.1159/000450623.CrossRefPubMed

23.

Abdul Sater H, Marte JL, Donahue RN, Walter-Rodriguez B, Heery CR, Steinberg SM, et al. Neoadjuvant prostvac prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-000655.CrossRefPubMedPubMedCentral

24.

Hum L, Bethmann D, Feng Z, Chang SC, Eckert A, Ballesteros-Merino C, et al. Cumulative suppressive index as a predictor of relapse free survival and overall survival in human papilloma virus-negative oral squamous cell carcinomas with negative resection margins. Head Neck. 2021;43(2):568–76. https://doi.org/10.1002/hed.26520.CrossRefPubMed

25.

Shibutani M, Maeda K, Nagahara H, Fukuoka T, Matsutani S, Kashiwagi S, et al. A Comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study. BMC Cancer. 2018;18(1):371. https://doi.org/10.1186/s12885-018-4276-y.CrossRefPubMedPubMedCentral

26.

Yu J, Green MD, Li S, Sun Y, Journey SN, Choi JE. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021;27(1):152–64. https://doi.org/10.1038/s41591-020-1131-x.CrossRefPubMedPubMedCentral

27.

McLane LM, Abdel-Hakeem MS, Wherry EJ. Cd8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457–95. https://doi.org/10.1146/annurev-immunol-041015-055318.CrossRefPubMed

28.

Ni YH, Ding L, Huang XF, Dong YC, Hu QG, Hou YY. Microlocalization of Cd68+ tumor-associated macrophages in tumor stroma correlated with poor clinical outcomes in oral squamous cell carcinoma patients. Tumour boil. 2015;36(7):5291–8. https://doi.org/10.1007/s13277-015-3189-5.CrossRef

29.

Yeung OWH, Lo C-M, Ling C-C, Qi X, Geng W, Li C-X, et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015;62(3):607–16. https://doi.org/10.1016/j.jhep.2014.10.029.CrossRefPubMed

30.

Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22(8):1865–74. https://doi.org/10.1158/1078-0432.CCR-15-1507.CrossRefPubMed

31.

Parra ER, Zhai J, Tamegnon A, Zhou N, Pandurengan RK, Barreto C, et al. Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues. Sci Rep. 2021;11(1):4530. https://doi.org/10.1038/s41598-021-83858-x.CrossRefPubMedPubMedCentral

32.

Saldarriaga OA, Freiberg B, Krishnan S, Rao A, Burks J, Booth AL, et al. Multispectral imaging enables characterization of intrahepatic macrophages in patients with chronic liver disease. Hepatol Commun. 2020;4(5):708–23. https://doi.org/10.1002/hep4.1494.CrossRefPubMedPubMedCentral

33.

Saleh R, Taha RZ, Toor SM, Sasidharan Nair V, Murshed K, Khawar M, et al. Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer. Cancer Immunol Immunother. 2020;69(10):1989–99. https://doi.org/10.1007/s00262-020-02593-w.CrossRefPubMedPubMedCentral

34.

Zhou SN, Pan WT, Pan MX, Luo QY, Zhang L, Lin JZ, et al. Comparison of immune microenvironment between colon and liver metastatic tissue in colon cancer patients with liver metastasis. Dig Dis Sci. 2021;66(2):474–82. https://doi.org/10.1007/s10620-020-06203-8.CrossRefPubMed

35.

Wu Y, Yang S, Ma J, Chen Z, Song G, Rao D, et al. Spatiotemporal immune landscape of colorectal cancer liver metastasis at single-cell level. Cancer Discov. 2021. https://doi.org/10.1158/2159-8290.CD-21-0316.CrossRefPubMedPubMedCentral

36.

Giese MA, Hind LE, Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood. 2019;133(20):2159–67. https://doi.org/10.1182/blood-2018-11-844548.CrossRefPubMedPubMedCentral

37.

Zeng X, Ward SE, Zhou J, Cheng ASL. Liver immune microenvironment and metastasis from colorectal cancer-pathogenesis and therapeutic perspectives. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13102418.CrossRefPubMedCentral

38.

Chandra R, Karalis JD, Liu C, Murimwa GZ, Voth Park J, Heid CA, et al. The colorectal cancer tumor microenvironment and its impact on liver and lung metastasis. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13246206.CrossRefPubMedCentral

39.

Berthel A, Zoernig I, Valous NA, Kahlert C, Klupp F, Ulrich A, et al. Detailed resolution analysis reveals spatial T cell heterogeneity in the invasive margin of colorectal cancer liver metastases associated with improved survival. Oncoimmunology. 2017;6(3): e1286436. https://doi.org/10.1080/2162402X.2017.1286436.CrossRefPubMedPubMedCentral

40.

Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18(1):64. https://doi.org/10.1186/s12943-019-0976-4.CrossRefPubMedPubMedCentral

41.

Wu L, Zhang XH. Tumor-associated neutrophils and macrophages-heterogenous but not chaotic. Front Immunol. 2020;11:553967. https://doi.org/10.3389/fimmu.2020.553967.CrossRefPubMedPubMedCentral

42.

Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (regonivo, Epoc1603). J Clin Oncol. 2020;38(18):2053–61. https://doi.org/10.1200/jco.19.03296.CrossRefPubMed

Title: Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases
Authors: Yangsong He
Yanan Han
A-hui Fan
Danxiu Li
Boda Wang
Kun Ji
Xin Wang
Xiaodi Zhao
Yuanyuan Lu
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Metastasis
Colorectal Cancer
Colorectal Cancer
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03667-2

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