Biology subjects

Davila, E.

Publications and source records attributed to Davila, E..

5 recordsLinked to original sources

bioRxiv2026

BCL11B targeting in tumor CD8+ T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity

Tumor infiltrating CD8+ T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low BCL11B mRNA. In line with this, ablation of Bcl11b in CD8+ TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. Bcl11b KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, Bcl11b KO CD8+ T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use. HIGHLIGHTS- Adoptive transfer of Bcl11b KO CD8+ TILs surpasses WT in tumor burden reduction - Bcl11b ablation reprograms TILs and impairs the progression to Ttex state - Bcl11b KO CD8+ T cells have elevated cytotoxicity and kill only Ag-MHCI targets - BCL11B deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1 GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/742578v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@c3b965org.highwire.dtl.DTLVardef@1c09d75org.highwire.dtl.DTLVardef@a19748org.highwire.dtl.DTLVardef@d2fd6b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Decitabine reverses innate immune gene suppression in rare melanomas

Rare melanoma subtypes, including acral, mucosal, and uveal melanomas, exhibit limited responses to immune checkpoint inhibitors (ICIs), yet the molecular mechanisms of immune resistance remain poorly defined. Here, we performed transcriptomic profiling of patient-derived xenografts (PDXs) and publicly available tumor datasets to systematically compare intratumoral gene expression across cutaneous and rare melanoma subtypes. We identified a convergent downregulation of innate immune pathogen sensing (IIPS) and type I interferon signaling pathways in rare melanomas compared to cutaneous, with lower expression also observed in anti-PD-1 non-responder tumors. CIBERSORT deconvolution of immune populations revealed that lower IIPS gene-expressing tumors exhibited reduced CD8 T cell and memory CD4 T cell infiltration, and enrichment of M2 macrophages, consistent with a more immunosuppressive tumor microenvironment. In vitro screening of epigenetic and immunomodulatory compounds revealed that the DNA hypomethylating agent decitabine robustly induced IIPS and adaptive immune gene expression in rare melanoma cell lines. In vivo treatment of mucosal and uveal melanoma xenograft models with decitabine resulted in durable upregulation of IIPS and antigen presentation genes, and whole transcriptome analysis confirmed that IIPS gene re-expression was the dominant transcriptional consequence of decitabine treatment. These findings highlight silencing of IIPS genes as a recurrent immune evasion mechanism in rare melanomas and nominate decitabine as a potential immunomodulatory strategy for enhancing immune responsiveness.

cancer biology↗

bioRxiv2025

Active surveillance of cats and dogs from households with human COVID-19 cases reveals over one quarter of pets infected with SARS-CoV-2 in 2020-2021 in Texas, United States

Households where people have COVID-19 are high risk environments for companion animals that are susceptible to SARS-CoV-2. We sampled 579 pets from 281 households with one or more laboratory-confirmed person with COVID-19 in central Texas from June 2020 to May 2021. Nineteen out of 396 (4.8%) dogs and 21 out of 157 (13.4%) cats were positive for SARS-CoV-2 by RT-qPCR. Additionally, 95/382 (25%) dogs and 52/146 (36%) cats harbored SARS-CoV-2 neutralizing antibodies. Twenty-six companion animals of ten other species were negative. Overall, 164 (29%) pets were positive for SARS-CoV-2 by molecular and/or serological tests; a total of 110 (39%) out of 281 households had at least one animal with active or past SARS-CoV-2 infection. Cats were more likely to be infected by SARS-CoV-2 and had higher endpoint antibody titers than dogs. Through viral isolation from a subset of respiratory swabs, we documented 6 different lineages in dogs and cats, including the B.1.1 lineage in a cat one month prior to the first known human case in the country. We observed animal and human-pet interaction factors associated with higher risk of infection for dogs and cats, such as days after COVID-19 diagnosis and sharing food. Frequency of clinical signs of disease reported by owners of pets with active infections did not differ from uninfected ones, suggesting that not all reported signs are attributed to SARS-CoV-2 infection. Characterizing animal infections using active SARS-CoV-2 surveillance in pets at risk of infection may aid in One Health pandemic prevention, response, and management.

microbiology↗

bioRxiv2024

The Porcine Skin Microbiome Exhibits Broad Fungal Antagonism

The skin and its microbiome function to protect the host from pathogen colonization and environmental stressors. In this study, using the Wisconsin Miniature Swine model, we characterize the porcine skin fungal and bacterial microbiomes, identify bacterial isolates displaying antifungal activity, and use whole-genome sequencing to identify biosynthetic gene clusters encoding for secondary metabolites that may be responsible for the antagonistic effects on fungi. Through this comprehensive approach of paired microbiome sequencing with culturomics, we report the discovery of novel species of Corynebacterium and Rothia. Further, this study represents the first comprehensive evaluation of the porcine skin mycobiome and the evaluation of bacterial-fungal interactions on this surface. Several diverse bacterial isolates exhibit potent antifungal properties against fungal pathogens in vitro. Genomic analysis of inhibitory species revealed a diverse repertoire of uncharacterized biosynthetic gene clusters suggesting a reservoir of novel chemical and biological diversity. Collectively, the porcine skin microbiome represents a potential unique source of novel antifungals. HighlightsO_LIPorcine skin bacterial communities are consistent with previous reports on porcine and human skin. C_LIO_LIFungal community composition resembles mycobiomes from other mammalian skin, but not human skin. C_LIO_LIBacteria isolated from porcine skin have antimicrobial and particularly strong antifungal activity in vitro. C_LIO_LIDiscovered three new Corynebacterium species and one new Rothia species. C_LI

microbiology↗

bioRxiv2020

Natural SARS-CoV-2 infections, including virus isolation, among serially tested cats and dogs in households with confirmed human COVID-19 cases in Texas, USA

The natural infections and epidemiological roles of household pets in SARS-CoV-2 transmission are not understood. We conducted a longitudinal study of dogs and cats living with at least one SARS-CoV-2 infected human in Texas and found 47.1% of 17 cats and 15.3% of 59 dogs from 25.6% of 39 households were positive for SARS-CoV-2 via RT-PCR and genome sequencing or neutralizing antibodies. Virus was isolated from one cat. The majority (82.4%) of infected pets were asymptomatic. Re-sampling of one infected cat showed persistence of viral RNA at least 32 d-post human diagnosis (25 d-post initial test). Across 15 antibody-positive animals, titers increased (33.3%), decreased (33.3%) or were stable (33.3%) over time. A One Health approach is informative for prevention and control of SARS-CoV-2 transmission.

zoology↗