Biology subjects

Kelley, R. K.

Publications and source records attributed to Kelley, R. K..

6 recordsLinked to original sources

bioRxiv2026

Identification of TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by CAR-T cell therapy

Background & Aims: Biliary tract cancers (BTCs) are a rare set of genetically heterogenous and aggressive malignancies associated with delayed presentation and poor prognosis. Thus, there is an unmet clinical need for the development of novel therapeutic strategies. Identification of uniquely expressed cell-surface, tumor-associated antigens (TAAs) holds promise in epithelial tumors more generally, as they can serve as ligands for a variety of therapeutics, including CAR-T cell therapy. However, TAA identification in BTCs has been limited by expression in normal liver tissue. Here, we aim to characterize the cell-surface protein transmembrane 4 L six family member 1 (TM4SF1) as a potential BTC TAA targetable by CAR-T therapy. Methods: TM4SF1 expression in BTC relative to normal hepatic/biliary tissue was characterized at the mRNA level by analyzing TCGA datasets and at the protein level by immunohistochemistry of archival primary BTC tissue. Anti-TM4SF1 CAR-T cells were evaluated through in vitro coculture assays against human-derived BTC cell lines and in a cell line-derived xenograft (CDX) model. Results: We find TM4SF1 is significantly upregulated in BTC relative to normal hepatic/biliary tissue and across BTC anatomical subtypes at the mRNA and protein level. To validate TM4SF1 as a targetable TAA in BTC, we show anti-TM4SF1 CAR-T cells demonstrate robust growth inhibition of BTC cell lines in vitro and significant anti-tumor activity against a CDX in vivo. Conclusions: Together, our data provides support for TM4SF1 as a promising TAA in BTCs that can be used for the rational development of targeted therapeutic modalities, including CAR-T cells, in a patient population with significant unmet need.

cancer biology↗

bioRxiv2025

Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer

Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYCs ability to reprogram cancer cell metabolism, and the livers role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

cancer biology↗

bioRxiv2025

Clinical and molecular characterisation of primary refractoriness to atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma.

BackgroundDespite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant and poorly understood clinical challenge. MethodsWe analysed 1296 patients with HCC and Child-Pugh A liver cirrhosis treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria as progressive disease in the first 6 months after treatment initiation. Patients who achieved complete response, partial response or stable disease for [≥] 6 months were classified as responders. We performed a multi-parametric analysis of pre-treatment tumour tissue including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. We employed conditional inference tree analyses to provide a hierarchical organisation of determinants of PRef. ResultsAmong 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months, HR 3.7, 95%CI 2.8-8.5, p<0.001; Trials: 10.8 vs. NR, HR 4.6, 95%CI 3.3-6.3, p<0.001). PRef patients exhibited higher baseline systemic inflammation (neutrophil-to-lymphocyte ratio, NLR [≥]3), a distinctively immunosuppressive TME enriched in CD163+ tumour-associated macrophages and a higher Treg/Teff ratio. RNAseq of tumour tissue demonstrated lower intrinsic immunogenicity in PRef samples, characterised by repressed IFN-{gamma} and Teff signatures, with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-{gamma} signature downregulation combined with NLR [≥]3 as the strongest contributor of PRef. ConclusionsPRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid cell infiltration and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-{gamma} signature expression and elevated NLR might enhance responsiveness to A+B. HighlightsO_LIPrimary refractoriness to atezolizumab plus bevacizumab in hepatocellular carcinoma, as defined by SITC criteria, is associated with poor clinical outcomes. C_LIO_LITumour microenvironment profiling reveals an immunosuppressive phenotype characterized by high myeloid infiltration, reduced interferon-{gamma} signalling, and T-cell depletion. C_LIO_LIThe combination of systemic inflammation and low IFN-{gamma} signature expression strongly predicts primary refractoriness and may inform therapeutic decision-making. C_LI

cancer biology↗

bioRxiv2024

Generation of a biliary tract cancer cell line atlas reveals molecular subtypes and therapeutic targets

Biliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.

cancer biology↗

bioRxiv2023

HBV rewires liver cancer signaling by altering PP2A complexes

Infection by hepatitis B virus (HBV) increases risk for liver cancer by inducing inflammation, cellular stress and cell death. To elucidate the molecular pathways by which HBV promotes cancer development and progression, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human host proteins in hepatocellular carcinoma (HCC). We find that viral proteins target host factors that are preferentially mutated in non-HBV-associated HCC, implicating cancer pathways whose interaction with HBV plays a role in HCC. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we show that HBx remodels the PP2A phosphatase complex, altering its effect on tumor signaling. HBx excludes striatin-family regulatory subunits from PP2A, causing Hippo kinase activation and unmasking a requirement for mTOR complex 2 to maintain expression of the YAP oncoprotein in HCC. Thus, HBV rewires HCC to expose potentially targetable signaling dependencies. SignificancePrecision medicine has revolutionized cancer treatment but remains elusive for HCC. We used proteomics to define HBV/host interactions and integrated them with HCC mutations. The results implicate modifiers of HCC behavior via remodeling of host complexes and illuminate new biological mechanisms in advanced disease for therapeutic investigation.

cancer biology↗

bioRxiv2021

A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that persistent tumors differentially engage inherent patterns-here Archetypes-of the immune system, to both benefit from a tumor immune microenvironment (TIME) and to disengage tumor-targeting. To discover dominant immune system archetypes, the Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub compartments uncovered archetypes that exist across indications. These Immune composition-based archetypes differentiate tumors based upon unique immune and tumor gene-expression patterns. Archetypes discovered this way also tie closely to well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune infiltration and provides a rational path forward to learn how to modulate these patterns to improve therapy. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/441344v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@55a5ccorg.highwire.dtl.DTLVardef@f8205corg.highwire.dtl.DTLVardef@1480b8org.highwire.dtl.DTLVardef@eb94e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗