Biology subjects

Aguilo, N.

Publications and source records attributed to Aguilo, N..

4 recordsLinked to original sources

bioRxiv2026

ST8SIA4-mediated polysialylation is critical for CCR2-driven monocyte egress from the bone marrow

Polysialylation is a rare post-translational protein modification essential for brain development and synaptic plasticity, where it fine-tunes cell-cell and cell-matrix interactions to direct neuronal migration, neurite outgrowth and synaptogenesis. Although polysialic acid is also expressed on circulating leukocytes, its functions in the immune system remain largely unexplored. Guided by analysis of publicly available human genomic data showing that naturally occurring variants of ST8SIA4, which encodes one of the two enzymes that mediate polysialylation, associate with reduced circulating monocyte counts, we investigated the in vivo role of this enzyme in monocyte biology. Using St8sia4-deficient mice, we show that ST8SIA4-dependent polysialylation is essential for CCR2-mediated egress of inflammatory monocytes from the bone marrow at steady state and during Mycobacterium tuberculosis infection. We confirm NCAM1 as the principal polysialylated protein in inflammatory monocytes and demonstrate that Ncam1-deficient mice phenocopy the monocyte defects observed in St8sia4-deficient animals. Mechanistically, loss of ST8SIA4-dependent polysialylation impairs engagement and internalization of the CCR2 ligands CCL2 and CCL7, accompanied by disrupted CCR2 surface organization and extensive cytoskeletal remodeling. Together, these findings identify polysialylation as a previously unrecognized regulator of CCR2 function and monocyte mobilization, with broad implications for immune surveillance and inflammatory responses. Highlights- Human ST8SIA4 variants are associated with reduced blood monocyte and lymphocyte counts and increased risk of SLE. - St8sia4-/- mice exhibit monocytopenia with impaired CCR2-mediated egress of inflammatory monocytes from the bone marrow both at steady state and during Mycobacterium tuberculosis infection. - ST8SIA4 polysialylates NCAM1 (CD56) in inflammatory monocytes, and Ncam1-/- - mice phenocopy the monocytopenia observed in St8sia4-/- mice. - Loss of ST8SIA4 and polysialylation impairs CCR2-mediated binding and endocytosis of CCL2 and CCL7 by monocytes. - Polysialic acid itself does not function as a co-receptor for these chemokines, revealing a new paradigm for its role in immune cell trafficking. - Proper CCR2 surface distribution and function, as well as cytoskeletal organization in inflammatory monocytes, depend on ST8SIA4-mediated polysialylation.

immunology↗

bioRxiv2025

BCG-induced reprogramming of monocyte/macrophage populations enhances lung antitumor immunity in mice

The tumor microenvironment (TME) significantly influences antitumor immunity, with monocytes and macrophages playing pivotal roles both in pro- and anti-tumoral functions. Tumor-associated macrophages (TAMs) often adopt immunosuppressive phenotypes that promote tumor progression by inhibiting cytotoxic T and NK cells. This study investigates the antitumor mechanisms of intravenous (IV) Bacillus Calmette-Guerin (BCG) in a B16-F10 lung melanoma mouse model, focusing on its impact on monocyte/macrophage populations. Single-cell RNA sequencing revealed that IV BCG reprograms tumor-associated monocyte-derived macrophages (mo-macs), shifting them from immunosuppressive to pro-inflammatory phenotypes enriched in interferon-response signatures. BCG treatment increased the recruitment of classical (Mon Iigp1) and non-classical (Mon Fcgr4) monocytes, which exhibited enhanced antigen presentation and pro-inflammatory cytokine production, while reducing immunosuppressive subsets prevalent in untreated controls. These BCG-induced mo-macs established robust interactions with NK and T cells, promoting their activation and enhancing cytotoxic function, as validated by functional assays. Notably, transfer of BCG reprogrammed bone marrow progenitors into naive recipients elicited a sustained generation of immunostimulatory mo-macs that enhanced NK and T cell responses upon tumor challenge, These findings highlight IV BCGs potential as a cancer immunotherapy that targets the myeloid compartment to foster a pro-inflammatory TME, offering durable antitumor immunity by engaging both innate and adaptive immune responses.

immunology↗

bioRxiv2024

NK cells mediate preventive efficacy of intravenous BCG against lung metastasis in mice

Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette-Guerin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-{gamma}) to tumor resistance. Tumor cells exposed to IFN-{gamma} upregulated were more resistant to BCG in vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-{gamma} signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.

immunology↗

bioRxiv2020

Natural killer activation for bladder cancer elimination can be achieved in vitro by heat-killed BCG

Immunotherapy, via intravesical instillations of Bacillus Calmette-Guerin (BCG) is the therapy of choice for patients with high risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, induces a local immune response that contributes to eliminate these tumours. The history of BCG development resulted in a large number of genetically diverse BCG substrains which could stimulate the immune system in different ways. Here, while investigating the capacity of different BCG substrains to promote the activation of NK cells, we confirmed that all the evaluated substrains could activate a cytotoxic CD56bright NK cell population which efficiently degranulated against bladder cancer cells; Tice, Connaught and Moreau were the substrains having a stronger effect. Dead mycobacteria also stimulated PBMC cultures and we demonstrate that subcellular fractions of BCG-Tice could contribute to the induction of this NK cell response. Lipids from BCG-Tice, but not from Mycobacterium bovis, stimulated NK cell activation and degranulation, however the aqueous fraction of either bacteria did not activate lymphocytes. Delipidated BCG-Tice activated effector cells (CD3+CD56+ and NK). These data suggest that different immune subpopulations could be stimulated using different fractions of mycobacteria for cancer elimination.

immunology↗