Biology subjects

Ferris, R.

Publications and source records attributed to Ferris, R..

4 recordsLinked to original sources

bioRxiv2026

Integrative multi-omic analysis identifies tumor-intrinsic p38 as a driver of immune exclusion in human epithelial cancers

Patients with tumors not responding to immune-checkpoint inhibition (ICI) often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-{gamma}-associated CD8+ T cells and dendritic cell activation. While the role of p38 mitogen-activated protein kinases (MAPKs) in regulating dendritic and myeloid cells is established, the tumor-intrinsic immunomodulatory function of p38 remains underexplored. Here, we identify tumor cell-intrinsic p38 signaling as a target candidate associated with immune exclusion and reduced immunotherapy response. In human papillomavirus-negative head and neck squamous carcinoma (HNSCC), molecular analysis of 395 tumor tissues revealed a p38-centered network enriched in non-T cell-inflamed tumors. Multi-cancer single-cell RNA sequencing analysis of over 200,000 cells further identifies p38 activation as a potential immune-exclusion program across multiple epithelial tumor types, including HNSCC and lung squamous cell carcinoma (LUSC), supported by tissue validation in [~]250 human biospecimens using multispectral imaging and digital spatial profiling. Functional studies demonstrate that p38 knockdown or pharmacologic inhibition in HNSCC and LUSC cell lines increases T cell migration, with CXCL16 identified as a chemokine mediator in vitro; neutralization of CXCL16 attenuated this effect. Together, these findings identify tumor-intrinsic p38 activation as a driver of immune exclusion in epithelial cancers and support its potential as a therapeutic target to overcome immunotherapy resistance.

Cancer Biology↗

bioRxiv2024

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+ T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

cancer biology↗

bioRxiv2021

An instance-specific causal framework for learning intercellular communication networks that define microenvironments of individual tumors

Cells within a tumor microenvironment (TME) dynamically communicate and influence each others cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor-specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.

cancer biology↗

bioRxiv2020

CREBBP/EP300 mutation is associated with poor outcome in HNSCC and targetable with synthetic cytotoxicity.

Despite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiation sensitizers for clinical use. We performed in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identified the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirmed this phenomenon was due to repression of homologous recombination following DNA damage and can be reproduced using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targets by HAT inhibition. Additionally, mutations in CREBBP/EP300 were associated with recurrence following radiation, in several squamous cell carcinoma cohorts. These findings represent both a novel mechanism of treatment resistance and the potential for genomically-driven treatment.

cancer biology↗