Biology subjects

Mehta, J. H.

Publications and source records attributed to Mehta, J. H..

3 recordsLinked to original sources

bioRxiv2025

Collagen remodeling promotes a GPCR-mediated mechanosensory immune checkpoint in ADGRG1+ CD8+ T cells and serves as a spatial biomarker of response to immunotherapy

Accessibility of immune cells to the tumor microenvironment (TME) in many solid tumors can be influenced by extracellular matrix (ECM) deposition, organization, and remodeling within tumor stroma. Specifically, lysyl hydroxylase-2 (LH2)-catalyzed lysine hydroxylation in type-I collagen telopeptides leads to formation of intermolecular collagen cross-links creating a stiffened and proteolytically resistant, stable ECM. Advanced head and neck squamous cell carcinomas (HNSCC) frequently exhibit desmoplasia with elevated LH2 expression, and Immune-checkpoint (ICI) therapy is effective in only <20% patients, suggesting that ECM remodeling mechanistically governs the composition and function of TME infiltrates. We show that elevated LH2 and collagen alignment promotes stromal accumulation of CD8 T-cells, and poor response to ICI in HPV-HNSCCs. Integration of clinical biopsies, transcriptomic datasets, and an immunocompetent syngeneic mouse model revealed that aligned collagen spatially restricts adhesion G protein-coupled receptor positive (ADGRG1) CD8 T-cells to activate a non-canonical GPCR-mediated mechanosensory program that drives dysfunction and exhaustion. Statement of significanceDesmoplasia is common in solid tumors, and immune checkpoint inhibitors benefit only some patients. Current biomarkers like PD-L1 and TMB have limited value. Our findings reveal a previously unrecognized collagen-ADGRG1 mechanosensory immune checkpoint, offering a clinically tractable, spatially resolved biomarker to better stratify patients for immunotherapy.

cancer biology↗

bioRxiv2025

Adaptive Responses Directed by CREB Control Epithelial-Mesenchymal Plasticity in Cancer

Cellular plasticity plays essential roles in development including organogenesis and tissue homeostasis. The epithelial-to-mesenchymal transition (EMT) is no longer considered a binary switch but rather a dynamic process characterized by a continuum of metastable intermediates having unique features. This epithelial-mesenchymal (E/M) plasticity can be co-opted by cancer cells to promote dedifferentiation that results in hybrid E/M states which increase tumor heterogeneity and generate distinct molecular and phenotypic adaptations that promote drug resistance, dormancy, recurrence, and/or cell invasion and metastasis. The mechanisms that coordinate and maintain metastable hybrid E/M states are poorly understood, and here we report they are controlled by the master transcription factor CREB which regulates adaptive response genes necessary for E/M plasticity. Specifically, a CREB-dependent head and neck cancer model validated the role of CREB in cancer cell plasticity and revealed that it controls a non-canonical EMT gene signature. Moreover, analyses of this signature across cancer types identified the transcriptional regulators VGLL3 and KLF3 as core PanCancer mediators of hybrid E/M states, and gain- and loss-of-function studies established that CREB regulates E/M plasticity by coordinating VGLL3 and KLF3 to drive metastasis.

cell biology↗

bioRxiv2022

Data availability of open T-cell receptor repertoire data, a systematic assessment

The improvement of next-generation sequencing technologies has promoted the field of immunogenetics and produced numerous immunogenomics data. Modern data-driven research has the power to promote novel biomedical discoveries through secondary analysis of such data. Therefore, it is important to ensure data-driven research with great reproducibility and robustness for promoting a precise and accurate secondary analysis of the immunogenomics data. In scientific research, rigorous conduct in designing and conducting experiments is needed, specifically in scientific and articulate writing, reporting and interpreting results. It is also crucial to make raw data available, discoverable, and well described or annotated in order to promote future re-analysis of the data. In order to assess the data availability of published T cell receptor (TCR) repertoire data, we examined 11,918 TCR-Seq samples corresponding to 134 TCR-Seq studies ranging from 2006 to 2022. Among the 134 studies, only 38.1% had publicly available raw TCR-Seq data shared in public repositories. We also found a statistically significant association between the presence of data availability statements and the increase in raw data availability (p=0.014). Yet, 46.8% of studies with data availability statements failed to share the raw TCR-Seq data. There is a pressing need for the biomedical community to increase awareness of the importance of promoting raw data availability in scientific research and take immediate action to improve its raw data availability enabling cost-effective secondary analysis of existing immunogenomics data by the larger scientific community.

scientific communication and education↗