Chemokine profiling of melanoma–macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma

Author:

Barrio‐Alonso Celia12ORCID,Nieto‐Valle Alicia12ORCID,García‐Martínez Elena3ORCID,Gutiérrez‐Seijo Alba12ORCID,Parra‐Blanco Verónica4ORCID,Márquez‐Rodas Iván5ORCID,Avilés‐Izquierdo José Antonio6ORCID,Sánchez‐Mateos Paloma27ORCID,Samaniego Rafael1ORCID

Affiliation:

1. Unidad de Microscopía Confocal Instituto de Investigación Sanitaria Gregorio Marañón Madrid Spain

2. Laboratorio de Inmuno‐oncología Instituto de Investigación Sanitaria Gregorio Marañón Madrid Spain

3. Servicio de Inmunología Hospital General Universitario Gregorio Marañón Madrid Spain

4. Servicio de Anatomía Patológica Hospital General Universitario Gregorio Marañón Madrid Spain

5. Servicio de Oncología Médica Hospital General Universitario Gregorio Marañón Madrid Spain

6. Servicio de Dermatología Hospital General Universitario Gregorio Marañón Madrid Spain

7. Departamento de Inmunología Universidad Complutense de Madrid Madrid Spain

Abstract

AbstractDuring cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor–macrophage co‐cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL8, CCL15, and CCL20, was actively secreted upon melanoma–macrophage co‐culture. Because we previously described the role of CCL20 in melanoma, we focused our study on CCL8 and CCL15 and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation, and 3D invasion through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis, and circulating tumor cell survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, using multicolor fluorescence and quantitative image analysis of chemokine–chemokine receptor content at the single‐cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and nonmetastatic cases. By contrast, comparative analysis of these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (p = 0.025) and CCL15 (p < 0.0001). Kaplan–Meier curves showed that a high content of CCL8 or CCL15 in cancer cells correlated with shorter disease‐free and overall survival (log‐rank test, p < 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma–macrophage interactions in biologically aggressive primary melanomas and could be clinically applicable biomarkers for patient profiling. © 2024 The Pathological Society of Great Britain and Ireland.

Funder

Ministerio de Ciencia e Innovación

Cancer Research UK

Publisher

Wiley

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Novel chemokine biomarkers in melanoma;The Journal of Pathology;2024-06-25

2. Immune Cell Migration to Cancer;Cells;2024-05-16

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