Biology subjects

Varela, I.

Publications and source records attributed to Varela, I..

5 recordsLinked to original sources

bioRxiv2023

VLP-mediated delivery of structure-selected neoantigens demonstrates immunogenicity and antitumoral activity in mice

BackgroundNeoantigens are patient- and tumor-specific peptides that arise from somatic mutations. They stand as promising targets for personalized therapeutic cancer vaccines. The identification process for neoantigens has evolved with the use of next-generation sequencing technologies and bioinformatic tools in tumor genomics. However, in silico strategies for selecting immunogenic neoantigens still have very low accuracy rates, since they mainly focus on predicting peptide binding to Major Histocompatibility Complex (MHC) molecules, which is key but not the sole determinant for immunogenicity. MethodsWe developed a novel neoantigen selection pipeline based on existing software combined with a novel prediction method, the Neoantigen Optimization Algorithm (NOAH), which takes into account structural features of the peptide/MHC-I interaction in its prediction strategy. Moreover, to maximize neoantigens therapeutic potential, neoantigen-based vaccines should be manufactured in an optimal delivery platform that elicits robust de novo immune responses and bypasses central and peripheral tolerance. ResultsWe generated a highly immunogenic vaccine platform based on engineered HIV-1 Gag-based Virus-Like Particles (VLPs) expressing a high copy number of each in silico selected neoantigen. We tested different neoantigen-loaded VLPs (neoVLPs) in a B16-F10 melanoma mouse model to evaluate their capability to generate new immunogenic specificities. NeoVLPs were used in in vivo immunogenicity and tumor challenge experiments. ConclusionsNeoVLPs can promote the generation of de novo antitumor-specific immune responses, resulting in a delay in tumor growth. Vaccination with the neoVLP platform is a robust alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy. WHAT IS ALREADY KNOWN ON THIS TOPICIdentification of highly immunogenic neoantigens is still challenging, currently available pipelines base their prediction on MHC-I binding affinity. Moreover, neoantigen-based vaccine delivery needs to be improved to increase the potency of anti-tumor immune response. WHAT THIS STUDY ADDSNOAH is a novel pipeline for the identification and selection of neoantigens that combines binding affinity and structural features of the peptide/MHC-I interaction. Preclinical studies show highly immunogenic vaccine platform based on HIV-1 Gag based VLPs (neoVLPs) generates antitumor-specific immune responses, delaying tumor growth. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe combination of NOAH and neoVLP platform represents an alternative to current therapeutic vaccine approaches and a promising candidate for future personalized immunotherapy.

immunology↗

bioRxiv2022

MYC directly transactivates CR2/CD21, the receptor of the Epstein-Barr virus, and enhances the viral infection of Burkitt lymphoma cells

The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that results in deregulated expression of MYC oncogene. This translocation is present in virtually all BL. MYC is an oncogenic transcription factor deregulated in about half of total human tumors, by translocation or other mechanisms. Transcriptomic studies reveal more than 1000 genes regulated by MYC but a much smaller fraction of these genes is directly activated by MYC. All the endemic BL and many sporadic BL cells are associated to the Epstein-Barr virus (EBV) infection. The currently accepted mechanism for the MYC and BL association is that EBV is the causing agent inducing MYC translocation. Complement receptor 2 or CR2 (also called CD21) is a membrane protein that serves as EBV receptor in lymphoid cells. Here we show that CR2 is a direct MYC target gene. This conclusion is based on several evidences. First, MYC downregulation is linked to CR2 downregulation both in proliferating and in arrested cells. Second, MYC binds human CR2 promoter and this binding depends on E-box elements. Third, MYC activates CR2 promoter in an E-box dependent manner. Four, MYC activates CR2 transcription in the absence of protein synthesis. Importantly, MYC also induces CR2 expression in mouse primary B cells. Thus, CR2 is a bona fide MYC direct target gene. Moreover, higher MYC expression levels in Burkitt lymphoma-derived cells result in a more efficient EBV infection. We propose an alternative mechanism compatible with the correlation between EBV infection and MYC translocation observed in endemic BL, i.e., that deregulated MYC in BL cells occurs first and favors the EBV infection.

cancer biology↗

bioRxiv2022

Generating parallel representations of position and identity in the olfactory system

Sex pheromones are key social signals in most animals. In Drosophila a dedicated olfactory channel senses a male pheromone, cis-vaccenyl acetate (cVA) that promotes female courtship while repelling males. Here we show that flies use separate cVA processing streams to extract qualitative and positional information. cVA olfactory neurons are sensitive to concentration differences in a 5 mm range around a male. Second-order projection neurons detect inter-antennal differences in cVA concentration, encoding the angular position of a male. We identify a circuit mechanism increasing left-right contrast through an interneuron which provides contralateral inhibition. At the third layer of the circuit we identify neurons with distinct response properties and sensory integration motifs. One population is selectively tuned to an approaching male with speed-dependent responses. A second population responds tonically to a males presence and controls female mating decisions. A third population integrates a male taste cue with cVA; only a simultaneous presentation of both signals promotes female mating via this pathway. Thus the olfactory system generates a range of complex percepts in discrete populations of central neurons that allow the expression of appropriate behaviors depending on context. Such separation of olfactory features resembles the mammalian what and where visual streams. HighlightsO_LIcVA male pheromone has a 5 mm signaling range, activating two parallel central pathways C_LIO_LIPheromone-sensing neurons have spatial receptive fields sharpened by contralateral inhibition C_LIO_LIPosition (where) and identity (what) are separated at the 3rd layer of cVA processing C_LIO_LIIntegrating taste and cVA in sexually dimorphic aSP-g controls female receptivity C_LI

neuroscience↗

bioRxiv2020

ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. Last decades research has evidenced a clear role of chromatin structure in cancer development and several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we have performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure, as well as functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. We have identified ARID2 production loss in 20% of lung cancer patients. Additionally, we have shown that ARID2-deficiency provokes profound chromatin structural changes, alters the transcriptional programme and impairs DNA repair which bolster the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we have demonstrated that ARID2 deficiency significantly affects the sensitivity of the cells to PARP inhibition. All these results support that ARID2 is a bona-fide tumor suppressor gene in lung cancer that might be exploited therapeutically.

cancer biology↗

bioRxiv2017

The MYC antagonist MNT autoregulates its expression and supports proliferation in MAX deficient cells

MNT is a transcription factor of the MXD family. MNT-MAX dimers down-regulate genes by binding to E-box sequences, which can also be bound by MYC-MAX to activate transcription. MNT has been described as a modulator of MYC activity but little is known about MNT regulation and whether MNT has MAX-independent functions. Using a MAX deficient cell line and siRNA-mediated silencing of MAX, we show that in the absence of MAX, the total MNT levels are elevated and that MNT localizes both in the cytoplasm and the nucleus. In contrast, MNT is predominantly nuclear when MAX is expressed. MNT is required for optimal cell proliferation even in the absence of MAX, being the first report of a MAX-independent function of MNT. Interestingly, MNT forms homodimers and autoregulates its expression by repressing its own promoter. The tight MNT regulation and its activity in absence of MAX suggest its importance on cell homeostasis.

cancer biology↗