Biology subjects

Figueiredo, C. R.

Publications and source records attributed to Figueiredo, C. R..

4 recordsLinked to original sources

bioRxiv2025

CD74 regulates antitumor immunity in melanoma by reprogramming dendritic cell immunogenicity and migration

Metastatic cutaneous melanoma remains a major therapeutic challenge, as many patients fail to respond or relapse following immune checkpoint therapy. The function of CD74, originally described as an MHC-II chaperone and receptor for macrophage migration inhibitory factor, remains poorly understood in tumor immunity. In this study, we show that systemic CD74 deletion in a syngeneic melanoma model significantly delayed tumor growth and reshaped the tumor immune microenvironment, and synergized with immune checkpoint blockade. Tumors in Cd74-/- mice had more effector and memory CD8+ T cells producing IFN-{gamma} and granzyme B than in control mice. Loss of CD74 promoted expansion of migratory cDC1s with elevated MHC-I and CCR7 expression. Cd74-/- professional antigen presenting cells increased cross-priming capacity for tumor-derived antigens in vivo and in vitro. Absence of CD74 induced the expression of CCR7, a key lymph node homing molecule, on cDCs and enhanced their ability to migrate towards the CCL19 ligand in single cell tracking analyses. These findings identify CD74 as a regulator of dendritic cell function and a promising therapeutic target to improve melanoma immunogenicity. One Sentence SummaryCD74 restrains cross-priming and migration capacity of dendritic cells, leading to impaired CD8+ T-cell infiltration and activation in tumor immunity.

immunology↗

bioRxiv2024

Secreted Clever-1 Modulates T Cell Responses and Impacts Cancer Immunotherapy Efficacy

Clever-1 functions as a scavenger and adhesion receptor, promoting tolerogenic activities in macrophages and subsets of endothelial cells, thereby contributing to cancer progression. High Clever-1 expression associates with resistance to immune checkpoint inhibitors and combined targeting of Clever-1 with anti-PD-1 enhances response in refractory mouse tumor models. A Clever-1-targeting humanized IgG4 antibody, bexmarilimab, is investigated in clinical trials as a macrophage-reprogramming therapy to treat solid tumors (NCT03733990) and hematological malignancies (NCT05428969). Here we describe a secreted form of (s)Clever-1 enriched in plasma of cancer patients, that was decreased upon bexmarilimab treatment. With the production of a recombinant sClever-1, mimicking the one found in human plasma, we show that sClever-1 can selectively bind activated T cells and disrupt T cell receptor signalling leading to impaired Th1 expansion. We demonstrate that sClever-1 binds to insulin growth factor 2 receptor (IGF2R) on T cells via its mannose-6-phosphate modification and further show that sClever-1 contributes to the immunosuppressive properties of macrophage-secreted extracellular vesicles, driving T cell tolerance and impairing anti-PD-1 efficacy. These findings suggest that Clever-1 exerts a systemic immunosuppressive effect independently of the cells it is expressed on, highlighting its potential as a target in cancer immunotherapy and a valuable biomarker for disease detection.

immunology↗

bioRxiv2021

The ORGAN SIZE (ORG) locus contributes to isometric gigantism in domesticated tomato

Gigantism is a key component of the domestication syndrome, a suite of traits that differentiates crops from their wild relatives. Allometric gigantism is strongly marked in horticultural crops, causing disproportionate increases in the size of edible parts such as stems, leaves or fruits. Tomato (Solanum lycopersicum) has attracted attention as a model for fruit gigantism, and many genes have been described controlling this trait. However, the genetic basis of a corresponding increase in size of vegetative organs contributing to isometric gigantism, has remained relatively unexplored. Here, we identified a 0.4 Mbp region on chromosome 7 in introgression lines (ILs) from the wild species Solanum pennellii in two different tomato genetic backgrounds (cv. M82 and cv. Micro-Tom) that controls vegetative and reproductive organ size in tomato. The locus, named ORGAN SIZE (ORG), was fine-mapped using genotype-by-sequencing. A survey of literature revealed that ORG overlaps with previously mapped QTLs controlling tomato fruit weight during domestication. Alleles from the wild species led to reduced cell number in different organs, which was partially compensated by greater cell expansion in leaves but not in fruits. The result was a proportional reduction in leaf, flower and fruit size in the ILs harbouring the wild alleles. These findings suggest that selection for large fruit during domestication also tends to select for increases in leaf size by influencing cell division. Since leaf size is relevant for both source-sink balance and crop adaptation to different environments, the discovery of ORG could allow fine-tuning of these parameters. One sentence summaryA locus that controls isometric size increase in vegetative and reproductive organs of tomato through changes in cell division

plant biology↗

bioRxiv2018

Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma.

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

cancer biology↗