Biology subjects

Vitorino, M.

Publications and source records attributed to Vitorino, M..

3 recordsLinked to original sources

bioRxiv2026

CCR4+low-density neutrophils define a novel immunosuppressive subset associated with breast cancer progression and early mortality

Neutrophils are increasingly recognized as key players in cancer progression, yet their functional heterogeneity limits their therapeutic exploitation. In breast cancer (BC), elevated circulating and tumor-associated neutrophils have been associated with poor prognosis, and low-density neutrophils (LDN), particularly, have been linked to immunosuppression. However, the specific neutrophil subsets driving these effects remain undefined. Here, we identify a previously unrecognized CCR4-expressing neutrophil subset, strongly enriched among LDN, whose frequency rises with disease stage and correlates with faster progression and shorter survival. Serial blood sampling further showed that CCR4+LDN levels fluctuate in line with clinical course, with increases indicating near-term risk in metastatic patients. Our findings also reveal that this subset has an immunosuppressive signature more pronounced than that of the remaining LDN, migrates preferentially toward tumor-derived chemokines, and dampens T cell-driven tumor killing even when PD-1 is blocked. Additionally, in a pilot cohort of Triple-Negative BC patients on anti-PD-1 therapy, early changes in this population were associated with treatment outcome. Together, these results reveal a distinct neutrophil population that actively contributes to immune escape and tumor progression, establishing CCR4+LDN as a minimally invasive real-time biomarker of disease course and treatment response, and as a promising target for neutrophil-directed therapies in BC.

immunology↗

bioRxiv2025

Neutrophils matter: New clinical insights on their role in the progression of metastatic breast cancer

BackgroundMetastatic breast cancer (BC) remains a significant clinical challenge, needing innovative strategies to improve disease management and extend patient survival. Increased neutrophil levels have been observed in both peripheral blood and tumor tissues of patients with different types of cancer, often being associated with poor clinical outcomes. These findings suggest a crucial role for neutrophils in tumor progression, raising interest in neutrophil-based therapies. However, the functional and phenotypic heterogeneity of neutrophils complicates their therapeutic targeting. This study aims to investigate the clinical impact of immunosuppressive, protumor low-density neutrophils (LDN) in metastatic BC, comparing them with normal high-density neutrophils (HDN) to better understand their role in disease progression. MethodsLDN and HDN subpopulations were isolated from the blood of 151 BC patients (72 metastatic, 79 non-metastatic) using density gradient centrifugation. Their frequency, phenotype, and function were analyzed by flow cytometry and in vitro experiments. Correlations between LDN levels and clinical data from metastatic BC patients were evaluated, alongside individual longitudinal assessments. ResultsLDN accumulated significantly in the blood of BC patients, particularly in those with metastatic disease. Elevated LDN levels in these patients were associated with faster disease progression and reduced life expectancy, regardless of metastatic site. Longitudinal analysis revealed that higher LDN percentages often correlated with adverse clinical events, whereas lower levels of LDN were linked to stable disease. Functionally, LDN exhibited protumor properties, including elevated expressions of PD-L1 and MMP-9, contributing to immunosuppression and metastasis. Unlike HDN, which demonstrated cytotoxicity against tumor cells, LDN failed to reduce BC cell line viability in 3D co-cultures. Notably, BC cell lines exposed to LDN-conditioned medium showed increased invasive capacity and proliferation, while T cells cultured in the same medium displayed impaired activation, likely due to the effect of arginase. ConclusionOur results highlighted LDN and their secreted factors as major drivers of BC progression and increased aggressiveness. These findings suggest that incorporating LDN assessment into clinical practice could aid in identifying high-risk patients and enable more personalized treatment approaches. Furthermore, our data strengthen the relevance of targeting specific neutrophil subsets or their functions to improve metastatic BC management and patient outcomes.

immunology↗

bioRxiv2024

Resistance to Carcinogenesis in the African Spiny Mouse (Acomys) correlates with upregulation of tumor suppressor genes.

Cancer remains a leading cause of morbidity and mortality worldwide, driving extensive research into the mechanisms that contribute to its development and progression. The search for animal models capable of shedding light on mechanisms of cancer resistance has led researchers to explore various rodent species. Among these, the African Spiny Mouse (Acomys sp.) has attracted considerable attention due to its regenerative abilities. In our study, we compared the response of Mus musculus and Acomys dimidiatus mice to treatment with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) combined with the inducer of proliferation 12-O-tetradecanoylphorbol-13-acetate (TPA). While both Acomys and Mus mice experienced carcinogenic damage to their skin cells, mounted proliferative responses and underwent immune cell infiltration, only Mus mice developed tumors, whereas Acomys remained tumor-free. To uncover the molecular mechanisms underlying this resistance, we performed RNA sequencing on tissue samples from both species at baseline and at multiple time points during the carcinogenesis protocol. The data reveal distinctly different transcriptional responses between both species. In particular, Acomys showed massive upregulation of immune related genes, including a set of tumor suppressor genes, while Mus seemed to focus its response on modifying epidermis structure and regulation of the cell cycle. These differences correlated with an increased apoptotic response in Acomys but not Mus. In summary, our study provides compelling evidence that Acomys mice exhibit remarkable resistance to tumor development under DMBA/TPA carcinogen treatment mediated through the upregulation of a range of processes related to immune surveillance.

cancer biology↗