A study from the La Fe Health Research Institute (IIS La Fe) has revealed that triple-negative breast cancer (TNBC) cells can reprogram macrophages, immune cells present in the tumor's microenvironment. These modified cells release inflammatory signals that facilitate cancer cell migration, survival, and lung colonization.
The research, led by the Translational Cancer Research group at IIS La Fe and the La Fe University Hospital and Polytechnic, and published in the scientific journal OncoImmunology, concludes that TNBC can 'educate' immune system cells to pave the way for lung metastasis. TNBC is one of the most aggressive forms of breast cancer, characterized by the absence of hormone receptors and HER2, which limits targeted treatment options and is associated with a higher capacity for dissemination and relapse.
The study provides an answer to the question of how some tumor cells manage to survive the journey through the body and establish themselves in distant organs. Researchers have observed that tumor cells modify their environment, converting macrophages into tumor-associated macrophages. These reprogrammed macrophages release cell communication signals, such as cytokines and chemokines CCL3, CCL4, CXCL2, and IL-1, which activate biological programs in tumor cells, increasing their ability to move, cross blood vessel walls, and colonize the lung.
Furthermore, this communication between tumor and macrophages also weakens the anti-tumor response. Reprogrammed macrophages promote the emergence of regulatory T cells, a type of immune cell that can reduce the defensive response against the tumor and reinforce an immunosuppressive microenvironment. María Rosado Sanz, a study author, explains that "this finding helps explain why some triple-negative breast tumors exhibit more aggressive behavior and poorer response to certain treatments." The work links the presence of immunosuppressive programs and pro-tumor macrophages with a worse response to neoadjuvant chemotherapy.
One of the relevant contributions is that researchers have demonstrated that blocking this communication reduces several processes necessary for tumor dissemination. By using inhibitors targeting receptors involved in this communication, such as maraviroc, navarixin, and anakinra, a reduction in tumor cell migration and lung colonization has been observed in preclinical models. Although these results require further clinical validation, the research opens a pathway for designing strategies to prevent the tumor from preparing the ground for metastasis.
The work offers a new perspective on cancer dissemination, where metastasis depends not only on the tumor's own characteristics but also on its ability to modify its surroundings and utilize immune system cells. In the case of TNBC, where metastatic relapse remains a significant clinical challenge, understanding these mechanisms is essential for developing more effective treatments and exploring future therapeutic combinations targeting the tumor microenvironment.
The research involved the participation of the La Fe Health Research Institute, the La Fe University Hospital and Polytechnic, the University of Valencia, the National Centre for Genomic Analysis, the University of Barcelona, and the Princess Máxima Center for Pediatric Oncology, among other collaborating institutions. It received support from the Association of Women Affected by Breast Cancer (AMACMA D8) of Requena, projects from the Ministry of Science, Innovation and Universities, the VLC-BIOMED 2024 program, predoctoral grants from the Scientific Foundation of the Spanish Association Against Cancer, Erasmus+, and the Generalitat Valenciana.
