Biology subjects

Park, A. K.

Publications and source records attributed to Park, A. K..

3 recordsLinked to original sources

bioRxiv2023

RETROFIT: REFERENCE-FREE DECONVOLUTION OF CELL-TYPE MIXTURES IN SPATIAL TRANSCRIPTOMICS

Spatial transcriptomics (ST) enables genome-wide measurement of gene expression in intact tissues, but typically captures mixtures of multiple cell types at each spatial location. Deconvolving these mixtures is essential for resolving cell-type-specific spatial organization and transcriptional programs. Existing approaches often rely on matched single-cell references or curated marker genes, which may be unavailable, incomplete, or difficult to integrate across platforms. We present RETROFIT, a Bayesian framework for reference-free deconvolution of spatial transcriptomics data that operates directly on sequencing measurements and incorporates external information only at a post hoc annotation stage when available. Across extensive simulations and multiple real datasets, RETROFIT demonstrates robust performance, outperforming existing reference-free methods and matching or exceeding reference-based approaches when references are imperfect. Notably, RETROFIT remains effective at near-single-cell resolution, as demonstrated on Visium HD data, recovering fine-grained spatial patterns without requiring single-cell references or marker genes. These results establish RETROFIT as a broadly applicable approach for reference-free spatial transcriptomics analysis across platforms and resolutions. RETROFIT is available at https://bioconductor.org/packages/retrofit/.

bioinformatics↗

bioRxiv2020

Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.

immunology↗

bioRxiv2019

Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors

Chimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of tumor-restricted and homogeneous expression of tumor antigens1,2. Therefore, we engineered an oncolytic virus to express a non-signaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-specific CAR T cells. Infecting tumor cells with a chimeric oncolytic vaccinia virus coding for CD19t (OV19t) produced de novo CD19 surface-antigen expression prior to virus-mediated tumor lysis. Co-cultured CD19-CAR T cells secreted cytokines and elicited potent cytolytic activity against infected tumors. Using multiple mouse tumor models, intratumoral delivery of OV19t induced tumor expression of CD19t and improved tumor control following CD19-CAR T cell administration. CAR T cell-mediated tumor killing also promoted release of virus from dying tumor cells, which propogated tumor expression of CD19t. These data demonstrate a novel immunotherapy approach utilizing oncolytic viruses to promote de novo CAR T cell targeting of solid tumors. One Sentence SummaryWe describe a novel and effective combination immunotherapy utilizing oncolytic viruses to deliver de novo cell surface expression of CD19 antigen promoting CD19-CAR T cell anti-tumor responses against solid tumors.

cancer biology↗