Biology subjects

Manriquez, V.

Publications and source records attributed to Manriquez, V..

6 recordsLinked to original sources

bioRxiv2025

Myeloid reprogramming by poly(I:C) recruits progenitor-exhausted CD8+ T cells and sensitizes rhabdoid tumors to PD-1 blockade

Immune exclusion remains a major barrier to effective immunotherapy in solid tumors. Given the abundance and plasticity of tumor-associated macrophages (TAMs) in many tumors, including pediatric tumors, we investigated whether TLR3 activation could reprogram them to facilitate immune access. Single-cell and spatial profiling in a mouse model of rhabdoid tumors showed that they are dominated by TLR3-expressing TAMs, whose depletion delays tumor growth. Treatment with the TLR3 agonist poly(I:C) promotes immune cell infiltration, including progenitor-exhausted CD8+ T cells, by multiple mechanisms including the reduction and reprogramming of immunosuppressive TAMs, promoting nitric-oxide production by peritumoral macrophages, and inducing CXCL9/10 production. Combined poly(I:C) and PD-1 blockade elicited durable, complete tumor rejection. Human macrophages from tumor biopsies showed conserved TLR3 responsiveness, underscoring translational potential. These findings uncover a mechanism by which TLR3-driven myeloid reprogramming transforms immune-excluded tumors into checkpoint-responsive ones, revealing a therapeutic path to overcome resistance to PD-1 blockade.

immunology↗

bioRxiv2025

Dual PD-L1/TIGIT blockade induces PNAd+ HEV-like vessels and CD62L+ lymphocyte recruitment, driving rhabdoid tumor rejection

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis and limited immunotherapy options. Here, we investigate the therapeutic potential of combined PD-L1 (Programmed cell death ligand 1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) immune checkpoint blockade in RTs using a preclinical murine model that recapitulates key features of human ATRT (Atypical teratoid rhabdoid tumors) subtypes. Transcriptomic analyses of human and murine RTs reveal co-expression of TIGIT and PD-1 (Programmed cell death 1) pathway components and their ligands, particularly in immune-infiltrated subtypes, supporting a rationale for dual blockade. Combination therapy induces complete tumor regression, prolongs survival, and reprograms the tumor immune microenvironment by enriching CD62L naive and central memory T cells and promoting selective T-cell clonal expansion. Notably, dual blockade initiates PNAd (Peripheral node addressin) high endothelial venule (HEV)-like structures, associated with focal lymphocyte clustering and enhanced immune cell recruitment. These findings reveal a mechanistic link between vascular remodeling and immune infiltration and support dual TIGIT and PD-L1 inhibition as a promising immunotherapeutic strategy for RTs.

immunology↗

bioRxiv2025

Macrophages restrict tumor permissiveness to immune infiltration by controlling local collagen topography through a Tcf4-Collagen3 fibrotic axis

During tumorigenesis, the extracellular matrix (ECM), which constitutes the structural scaffold of tissues, is profoundly remodeled. While the impact of such remodeling on tumor growth and invasion has been extensively investigated, much less is known on the consequences of ECM remodeling on tumor infiltration by immune cells. By combining tissue imaging and machine-learning, we here show that the localization of T lymphocytes and neutrophils, which orchestrate antitumor immune responses, can be predicted by defined topographical features of fibrillar collagen networks. We further show that these collagen topographies result from the activation of a fibrotic pathway controlled by the transcription factor Tcf4 upon depletion of tumor-associated macrophages at late tumor stages. This pathway promotes the deposition of collagen 3 by both tumor and stromal cells, resulting in intermingled collagen networks that favor intra-tumoral T cell and neutrophil localization. Importantly, analysis of human colorectal cancer public bulk RNAseq databases showed a strong correlation between Tcf4 and collagen 3, as well as between the expression of these genes and tumor infiltration by T lymphocytes and neutrophils, attesting the clinical relevance of our findings. This study highlights the key structural role of macrophages on the tumor extracellular matrix and identifies collagen network topographies as a major regulator of tumor infiltration by immune cells.

immunology↗

bioRxiv2021

Integrative genomics uncover mechanisms of renal medullary carcinoma transformation, microenvironment landscape and therapeutic vulnerabilities.

Renal medullary carcinoma (RMC) is an aggressive desmoplastic tumour driven by bi-allelic loss of SMARCB1, however the cell-of-origin, the oncogenic mechanism and the features of its microenvironment remain poorly understood. Using single-cell and multi-region sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into at least three RMC cell states along an epithelial-mesenchymal gradient through a transcriptional switch involving loss of renal transcription factor TFCP2L1 and gain of a NFE2L2-associated ferroptosis resistance program. SMARCB1 re-expression in cultured RMC cells reactivates TFCP2L1 that relocates SWI/SNF from the promoters of the MYC-driven oncogenic program to the enhancers of TAL identity genes followed by ferroptotic cell death. We further show that RMC is associated with abundant M2-type macrophages and cancer-associated fibroblasts (CAFs) and we identify key regulatory cross-talks that shape this immunosuppressive microenvironment. Together our data describe the molecular events of RMC transformation and identify novel therapeutically targetable vulnerabilities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/462391v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@152fa6eorg.highwire.dtl.DTLVardef@b76f50org.highwire.dtl.DTLVardef@ed1382org.highwire.dtl.DTLVardef@9be54f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Colonization of dermal arterioles by Neisseria meningitidis provides a safe haven from neutrophils

Neisseria meningitidis, a human-specific bacterium, is responsible for meningitis and fatal fulminant systemic disease. Bacteria colonize blood vessels, rapidly causing devastating vascular damage despite a neutrophil-rich inflammatory infiltrate. How this pathogen escapes the neutrophil response is unknown. Using a humanized mouse model, we show that vascular colonization leads to the recruitment of neutrophils, partially reducing bacterial burden and vascular damage. This partial effect is due to the ability of bacteria to indiscriminately colonize capillaries, venules and arterioles, as observed in human samples. In venules, potent neutrophil recruitment allows efficient bacterial phagocytosis. In contrast, in infected capillaries and arterioles adhesion molecules such as E-Selectin are not expressed on the endothelium and intravascular neutrophil recruitment is minimal. These results show that colonization of capillaries and arterioles by N. meningitidis create an intravascular niche that preclude the action of neutrophils, resulting in immune escape and subsequent fulminant progression of the infection.

microbiology↗

bioRxiv2018

Adhesion to nanofibers drives cell membrane remodeling through 1D wetting

The shape of cellular membranes is highly regulated by a set of conserved mechanisms. These mechanisms can be manipulated by bacterial pathogens to infect cells. Human endothelial cell plasma membrane remodeling by the bacterium Neisseria meningitidis is thought to be essential during the blood phase of meningococcal infection, but the underlying mechanisms are unknown. Here we show that plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers, by a novel physical mechanism we term \" onedimensional\" membrane wetting. We provide a theoretical model that gives the physical basis of 1D wetting and show that this mechanism occurs in model membranes interacting with model nanofibers, and in human cells interacting with model extracellular matrices. It is thus a new general principle driving the interaction of cells with their environment at the nanoscale that is diverted by meningococcus during infection.

cell biology↗