Biology subjects

O'Reilly, E. M.

Publications and source records attributed to O'Reilly, E. M..

5 recordsLinked to original sources

bioRxiv2026

Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB), although homologous recombination-deficient (HRD) tumors may derive benefit. In the POLAR trial of maintenance pembrolizumab plus olaparib after platinum-based chemotherapy for metastatic PC, responses remained heterogeneous. To define determinants of productive antitumor immunity, we integrated longitudinal blood TCR sequencing with tumor single-cell and spatial profiling. Durable benefit was associated with rare tumor-infiltrating, peripherally expanding (TIE) CD8+ T cell clonotypes, a subset of which were functionally neoantigen-reactive. TIE patients showed markedly prolonged survival beyond established genomic and immune biomarkers. Conversely, resistance was associated with spatial T cell exclusion, myCAF-rich stromal remodeling, basal-like/KRAS-associated malignant-cell programs, and expansion of CTLA4 regulatory T cells linked to local immunosuppressive remodeling. These findings define a clonotype-resolved framework for immune monitoring and identify complementary stromal, tumor-intrinsic, and regulatory immune barriers that may guide rational combination immunotherapy in PC.

cancer biology↗

bioRxiv2026

POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer

Pancreatic cancer (PC) is broadly resistant to immune checkpoint blockade, although a subset of homologous recombination-deficient (HRD) tumors exhibits durable immune engagement. The genomic features that distinguish these immune-responsive tumors from immune-inert HRD tumors remain poorly understood. Here we identify a microhomology-mediated end joining (MMEJ) repair scar, the MMEJ Deletion Footprint (MDF), as a genomic readout of POLQ-associated error-prone repair that enriches for frameshift indels. Across the multi-omic discovery cohort integrating tumor genomics, single-nucleus transcriptomics and spatial immune profiling, MDF-high HRD PC exhibited increased frameshift-indel-derived neoantigens and interferon programs. MDF was further associated with remodeling of the myeloid compartment toward MHC II-high dendritic cell-like antigen-presenting macrophage states and the immune synapse architecture marked by increased spatial interaction between APC-like macrophages and cytotoxic CD8+ T cells. These tissue-level features aligned with a functional trajectory shift of CD8+ T cells, consistent with effective anti-tumor immunity and was associated with favorable clinical outcomes of patients. Together, our findings position MMEJ-linked repair scarring as actionable biology that connects an HRD genotype to immune organization and suggests rational immunotherapy combinations that may enhance antigen presentation and myeloid activation to extend durable benefit in HRD-lineage cancers.

cancer biology↗

bioRxiv2025

Transcriptomic plasticity is a hallmark of metastatic pancreatic cancer

Metastasis is the leading cause of cancer deaths; nonetheless, how tumor cells adapt to vastly different organ contexts is largely unknown. To investigate this question, we generated a transcriptomic atlas of primary tumor and diverse metastatic samples from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy. Unsupervised archetype analysis identified both shared and site-specific gene programs, including lipid metabolism and gastrointestinal programs prevalent in peritoneum and stomach wall lesions, respectively. We developed a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome data. Distantly related genetic clones in the peritoneum express the lipid metabolism program, likely due to signaling by the adipocyte-rich peritoneum environment, and cells in most clones express multiple programs, suggesting that transcriptomic plasticity is a prevalent feature of metastatic cells. These deeply annotated analyses using a patient-centric platform provide a model for investigating metastatic mechanisms and plasticity in advanced cancer.

bioinformatics↗

bioRxiv2024

Genomic evolution of pancreatic cancer at single-cell resolution

We adapted a previously developed targeted single-nucleus DNA sequencing (snDNA-seq) method and constructed a new suite of computational analysis tools to study 137,491 single-nucleus DNA libraries from 24 pancreatic cancers collected under a variety of clinical scenarios including early and late diagnoses, different metastatic sites and before- and after-treatment. We refined the mutational landscape of pancreatic cancer by capturing events missed by bulk sequencing, and validated the evolution pattern of early fixation of driver single-nucleotide variants (SNVs) followed by generation of intratumoral heterogeneity for copy number variations (CNVs). Intertumoral convergent evolution was common, including subclonal inactivation of TGF-{beta} pathway by mutating various components of it; intratumoral convergence was rarely observed, likely due to strong selective force in pancreatic cancer development. Continuous evolution was frequently seen manifesting as CNVs. In the context of non-targeted treatments, no particular pattern was found across metastases or through treatment. In six pancreatic cancers with germline BRCA2 mutation, we discovered varied timing of biallelic inactivation of BRCA2, which sculpted different evolutionary trajectories and could presumably contribute to differential response to treatment. As the first large-scale application of targeted snDNA-seq on pancreatic cancer, this work provides a sample processing and computational analysis pipeline that warrants further clinical utility.

cancer biology↗

bioRxiv2021

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

cancer biology↗