Prognostic Significance of CD163+ And/or CD206+ Tumor-Associated Macrophages Is Linked to Their Spatial Distribution and Tumor-Infiltrating Lymphocytes in Breast Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Jun 19

PMID 38893266

Authors

Canbin Fang

Maisy Y Cheung

Ronald C Chan

Ivan K Poon

Conrad Lee

Curtis C To

Julia Y Tsang

Joshua Li

Gary M Tse

Affiliations

Soon will be listed here.

Abstract

Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors ( = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis ( = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) ( = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases.

References

Kuroda H, Jamiyan T, Yamaguchi R, Kakumoto A, Abe A, Harada O . Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes. Clin Transl Oncol. 2021; 23(12):2513-2525. PMC: 8557183. DOI: 10.1007/s12094-021-02652-3. View

Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F . Prognostic significance of tumor-associated macrophages in breast cancer: a meta-analysis of the literature. Oncotarget. 2017; 8(18):30576-30586. PMC: 5444766. DOI: 10.18632/oncotarget.15736. View

Soysal S, Tzankov A, Muenst S . Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015; 82(3-4):142-52. DOI: 10.1159/000430499. View

Lopez-Janeiro A, Padilla-Ansala C, de Andrea C, Hardisson D, Melero I . Prognostic value of macrophage polarization markers in epithelial neoplasms and melanoma. A systematic review and meta-analysis. Mod Pathol. 2020; 33(8):1458-1465. DOI: 10.1038/s41379-020-0534-z. View

Maisel B, Yi M, Peck A, Sun Y, Hooke J, Kovatich A . Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer. Cancers (Basel). 2022; 14(2). PMC: 8773496. DOI: 10.3390/cancers14020308. View

Roca H, Varsos Z, Sud S, Craig M, Ying C, Pienta K . CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009; 284(49):34342-54. PMC: 2797202. DOI: 10.1074/jbc.M109.042671. View

Strack E, Rolfe P, Fink A, Bankov K, Schmid T, Solbach C . Identification of tumor-associated macrophage subsets that are associated with breast cancer prognosis. Clin Transl Med. 2020; 10(8):e239. PMC: 7719284. DOI: 10.1002/ctm2.239. View

Elston C, Ellis I . Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991; 19(5):403-10. DOI: 10.1111/j.1365-2559.1991.tb00229.x. View

Laviron M, Petit M, Weber-Delacroix E, Combes A, Arkal A, Barthelemy S . Tumor-associated macrophage heterogeneity is driven by tissue territories in breast cancer. Cell Rep. 2022; 39(8):110865. DOI: 10.1016/j.celrep.2022.110865. View

10.

Chan R, Aphivatanasiri C, Poon I, Tsang J, Ni Y, Lacambra M . Spatial Distribution and Densities of CD103+ and FoxP3+ Tumor Infiltrating Lymphocytes by Digital Analysis for Outcome Prediction in Breast Cancer. Oncologist. 2023; 29(3):e299-e308. PMC: 10911924. DOI: 10.1093/oncolo/oyad199. View

11.

Kloosterman D, Akkari L . Macrophages at the interface of the co-evolving cancer ecosystem. Cell. 2023; 186(8):1627-1651. DOI: 10.1016/j.cell.2023.02.020. View

12.

Lepland A, Asciutto E, Malfanti A, Simon-Gracia L, Sidorenko V, Vicent M . Targeting Pro-Tumoral Macrophages in Early Primary and Metastatic Breast Tumors with the CD206-Binding mUNO Peptide. Mol Pharm. 2020; 17(7):2518-2531. DOI: 10.1021/acs.molpharmaceut.0c00226. View

13.

Goswami K, Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R . Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol. 2017; 316:1-10. DOI: 10.1016/j.cellimm.2017.04.005. View

14.

Mosser D, Edwards J . Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12):958-69. PMC: 2724991. DOI: 10.1038/nri2448. View

15.

Zheng X, Weigert A, Reu S, Guenther S, Mansouri S, Bassaly B . Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non-Small Cell Lung Carcinoma. Cancer Res. 2020; 80(20):4414-4425. DOI: 10.1158/0008-5472.CAN-20-0069. View

16.

Modak M, Mattes A, Reiss D, Skronska-Wasek W, Langlois R, Sabarth N . CD206+ tumor-associated macrophages cross-present tumor antigen and drive antitumor immunity. JCI Insight. 2022; 7(11). PMC: 9220841. DOI: 10.1172/jci.insight.155022. View

17.

Zwager M, Bense R, Waaijer S, Qiu S, Timmer-Bosscha H, de Vries E . Assessing the role of tumour-associated macrophage subsets in breast cancer subtypes using digital image analysis. Breast Cancer Res Treat. 2023; 198(1):11-22. PMC: 9883348. DOI: 10.1007/s10549-022-06859-y. View

18.

Kim Y, Wen X, Bae J, Kim J, Cho N, Kang G . The distribution of intratumoral macrophages correlates with molecular phenotypes and impacts prognosis in colorectal carcinoma. Histopathology. 2018; 73(4):663-671. DOI: 10.1111/his.13674. View

19.

Leek R, Lewis C, Whitehouse R, Greenall M, Clarke J, Harris A . Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 1996; 56(20):4625-9. 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