Exploratory Study of Macrophage Polarization and Spatial Distribution in Colorectal Cancer Liver Metastasis: a Pilot Study

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Aug 28

PMID 37637998

Authors

Isha Khanduri

Dipen M Maru

Edwin R Parra

Affiliations

Soon will be listed here.

Abstract

Background: The liver is the most typical site of metastatic disease for patients with colorectal cancer (CRC), and up to half the patients with CRC will develop colorectal liver metastasis (CLM). Studying the tumor microenvironment, particularly macrophages and their spatial distribution, can give us critical insight into treatment.

Methods: Ten CLMs (five treatment-naïve and five post-neoadjuvant chemotherapy) were stained with multiplex immunofluorescence panels against cytokeratins, CD68, Arg1, CD206, CD86, CD163, PD-L1, and MRP8-14. Densities of cell phenotypes and their spatial distribution in the tumor center and the normal liver-tumor interface were correlated with clinicopathological variables.

Results: M2 macrophages were the predominant subtype in both the tumor center and the periphery, with a relatively higher density at the periphery. The larger tumors, more than 3.9 cm, were associated with higher densities of total CD68+ macrophages and CD68+CD163+ CD206 and CD68+CD206+ CD163 M2 macrophage subtypes. Total macrophages in the tumor periphery demonstrated significantly greater proximity to malignant cells than did those in the tumor center (p=0.0371). The presence of higher than median CD68+MRP8-14+CD86 M1 macrophages in the tumor center was associated with poor overall survival (median 2.34 years) compared to cases with lower than median M1 macrophages at the tumor center (median 6.41 years) in univariate analysis.

Conclusion: The dominant polarization of the M2 macrophage subtype could drive new therapeutic approaches in CLM patients.

Citing Articles

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References

Yu C, Wortman J, He T, Solomon S, Zhang R, Rosario A . Physics approaches to the spatial distribution of immune cells in tumors. Rep Prog Phys. 2020; 84(2):022601. DOI: 10.1088/1361-6633/abcd7b. View

Speel E, Hopman A, Komminoth P . Amplification methods to increase the sensitivity of in situ hybridization: play card(s). J Histochem Cytochem. 1999; 47(3):281-8. DOI: 10.1177/002215549904700302. View

Lin E, Pollard J . Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 2007; 67(11):5064-6. DOI: 10.1158/0008-5472.CAN-07-0912. View

Stack E, Wang C, Roman K, Hoyt C . Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014; 70(1):46-58. DOI: 10.1016/j.ymeth.2014.08.016. View

Parra E, Jiang M, Solis L, Mino B, Laberiano C, Hernandez S . Procedural Requirements and Recommendations for Multiplex Immunofluorescence Tyramide Signal Amplification Assays to Support Translational Oncology Studies. Cancers (Basel). 2020; 12(2). PMC: 7072187. DOI: 10.3390/cancers12020255. View

Liu Y, Zugazagoitia J, Shabbir Ahmed F, Henick B, Gettinger S, Herbst R . Immune Cell PD-L1 Colocalizes with Macrophages and Is Associated with Outcome in PD-1 Pathway Blockade Therapy. Clin Cancer Res. 2019; 26(4):970-977. PMC: 7024671. DOI: 10.1158/1078-0432.CCR-19-1040. View

Taghizadeh H, Mader R, Mullauer L, Erhart F, Kautzky-Willer A, Prager G . Precision Medicine for the Management of Therapy Refractory Colorectal Cancer. J Pers Med. 2020; 10(4). PMC: 7768503. DOI: 10.3390/jpm10040272. View

Konstantinov A, Kovaleva O, Samoilova D, Shelekhova K . Role of macrophages in progression of colorectal cancer: a contrast with the traditional paradigm. Int J Clin Exp Pathol. 2022; 15(10):403-411. PMC: 9638838. View

Parra E . Methods to Determine and Analyze the Cellular Spatial Distribution Extracted From Multiplex Immunofluorescence Data to Understand the Tumor Microenvironment. Front Mol Biosci. 2021; 8:668340. PMC: 8226163. DOI: 10.3389/fmolb.2021.668340. View

10.

Zhu D, Johnson T, Wang Y, Thomas M, Huynh K, Yang Q . Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb. Stem Cell Res Ther. 2020; 11(1):162. PMC: 7178595. DOI: 10.1186/s13287-020-01669-9. View

11.

Parra E, Uraoka N, Jiang M, Cook P, Gibbons D, Forget M . Validation of multiplex immunofluorescence panels using multispectral microscopy for immune-profiling of formalin-fixed and paraffin-embedded human tumor tissues. Sci Rep. 2017; 7(1):13380. PMC: 5645415. DOI: 10.1038/s41598-017-13942-8. View

12.

Boutilier A, Elsawa S . Macrophage Polarization States in the Tumor Microenvironment. Int J Mol Sci. 2021; 22(13). PMC: 8268869. DOI: 10.3390/ijms22136995. View

13.

Tiainen S, Tumelius R, Rilla K, Hamalainen K, Tammi M, Tammi R . High numbers of macrophages, especially M2-like (CD163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology. 2014; 66(6):873-83. DOI: 10.1111/his.12607. View

14.

Cortese N, Soldani C, Franceschini B, Barbagallo M, Marchesi F, Torzilli G . Macrophages in Colorectal Cancer Liver Metastases. Cancers (Basel). 2019; 11(5). PMC: 6562719. DOI: 10.3390/cancers11050633. View

15.

Tang J, Rangayyan R, Xu J, El Naqa I, Yang Y . Computer-aided detection and diagnosis of breast cancer with mammography: recent advances. IEEE Trans Inf Technol Biomed. 2009; 13(2):236-51. DOI: 10.1109/TITB.2008.2009441. View

16.

Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N . Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci. 2012; 103(11):2012-20. PMC: 7659389. DOI: 10.1111/j.1349-7006.2012.02411.x. View

17.

Bobrow M, Harris T, Shaughnessy K, Litt G . Catalyzed reporter deposition, a novel method of signal amplification. Application to immunoassays. J Immunol Methods. 1989; 125(1-2):279-85. DOI: 10.1016/0022-1759(89)90104-x. View

18.

He Y, Han Y, Fan A, Li D, Wang B, Ji K . Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases. J Transl Med. 2022; 20(1):454. PMC: 9533561. DOI: 10.1186/s12967-022-03667-2. View

19.

Liu J, Geng X, Hou J, Wu G . New insights into M1/M2 macrophages: key modulators in cancer progression. Cancer Cell Int. 2021; 21(1):389. PMC: 8296555. DOI: 10.1186/s12935-021-02089-2. View

20.

Huang Y, Wang M, Sun Y, Di Costanzo N, Mitchell C, Achuthan A . Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nat Commun. 2019; 10(1):3928. PMC: 6718690. DOI: 10.1038/s41467-019-11788-4. View