Biology subjects

Chen, D.-T.

Publications and source records attributed to Chen, D.-T..

4 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↗

bioRxiv2024

Trastuzumab deruxtecan combination strongly enhances responses and overcomes sotorasib resistance in KRASG12C-mutant NSCLC

IntroductionRecent advances in the treatment of KRAS-mutant non-small cell lung cancer (NSCLC) have led to the development of KRASG12C inhibitors, such as sotorasib and adagrasib. However, resistance and disease progression remain significant challenges. In this study, we investigated the therapeutic potential of combining trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody-drug conjugate, with sotorasib in KRASG12C-mutant NSCLC, while also evaluating HER2 expression in NSCLC samples. MethodsThe HER2 expression dependence of xenograft responses to sotorasib, T-DXd, and their combination was evaluated in therapy-naive and sotorasib-treated tumors by immunohistochemistry (IHC). Also, we analyzed 191 clinical (pre- or on-treatment) and rapid autopsy (post-treatment) samples from 31 patients with driver-positive and driver-negative advanced stage NSCLC, assessing HER2 expression using interpretation guidelines developed for breast cancer (BC) and gastroesophageal adenocarcinoma (GEA). ResultsIn the majority of preclinical models, including sotorasib-resistant tumors, the sotorasib-T-DXd combination induced stronger and more durable responses compared to monotherapies. The strong effect of the combination therapy was likely attributable to sotorasib-induced adaptive HER2 upregulation; stronger HER2 expression in sotorasib-treated tumors was linked with stronger responses. Although HER2 expression was higher in samples from patients with KRASG12C-mutant NSCLC compared to NSCLC with other driver mutations or no drivers, the difference was not statistically significant. HER2 IHC score discrepancy was also observed between BC and GEA interpretation guidelines. ConclusionsOur results support the potential clinical utility of the sotorasib-T-DXd combination, including tumors with intrinsic and acquired resistance to sotorasib monotherapy. Since the strengths of the responses depend on HER2 expression levels, successful clinical implementation necessitates optimizing patient selection. Our results highlight the complexities of accurate HER2 interpretation in NSCLC and highlight the need for standardized testing methods.

cancer biology↗

bioRxiv2021

Utilizing Digital Pathology to Quantify Stromal Caveolin-1 Expression in Malignant and Benign Ovarian Tumors: Associations with Clinicopathological Parameters and Clinical Outcomes

Loss of stromal caveolin-1 (Cav-1) is a biomarker of a cancer-associated fibroblast (CAF) phenotype and is related to progression, metastasis, and poor outcomes in several cancers. The objective of this study was to evaluate the clinical significance of Cav-1 expression in invasive epithelial ovarian cancer (OvCa). Epithelial and stromal Cav-1 expression were quantified in serous OvCa and benign ovarian tissue in two, independent cohorts - one quantified expression using immunohistochemistry (IHC) and the other using multiplex immunofluorescence (IF) with digital image analysis designed to target CAF-specific expression. Cav-1 expression was significantly downregulated in OvCa stroma compared to non-neoplastic stroma using both the IHC (p=0.002) and IF (p=1.8x10-13) assays. OvCa stroma showed Cav-1 downregulation compared to tumor epithelium with IHC (p=1.2x10-24). Conversely, Cav-1 expression was higher in OvCa stroma compared to tumor epithelium with IF (p=0.002). There was moderate correlation between IHC and IF methods for stromal Cav-1 expression (r2= 0.69, p=0.006) whereas there was no correlation for epithelial expression (r2=0.006, p=0.98). Irrespective of the staining assay, neither response to therapy or overall survival correlated with the expression level of Cav-1 in the stroma or tumor epithelium. Our findings demonstrate a loss of stromal Cav-1 expression in ovarian serous carcinomas. Studies are needed to replicate these findings and explore therapeutic implications, particularly for immunotherapy response.

cancer biology↗

bioRxiv2020

Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas

Pancreatic cancer (PaCa) is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect PaCa at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic PaCa precursors that comprise nearly 50% of pancreatic cysts detected incidentally via cross-sectional imaging. Since IPMNs can progress from low- and moderate-grade dysplasia to high-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish a living biobank of patient-derived organoids (PDO) from IPMNs. IPMN tumors and adjacent normal pancreatic tissues were successfully harvested from 15 patients with IPMNs undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between May of 2017 and March of 2019. Organoid cultures were also generated from cryopreserved tissues. Organoid count and size were determined over time by both Image-Pro Premier 3D Version 9.1 digital platform and Matlab application of a Circular Hough Transform algorithm, and histologic and genomic characterization of a subset of the organoids was performed using immunohistochemistry and targeted sequencing, respectively. The success rates for organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different epithelial subtypes showed different morphologies in vitro, and organoids recapitulated histologic and genomic characteristics of the parental IPMN tumor. In summary, this pre-clinical model has the potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for early detection and targets for chemoprevention.

cancer biology↗