Biology subjects

Iacobuzio-Donahue, C.

Publications and source records attributed to Iacobuzio-Donahue, C..

4 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↗

bioRxiv2023

Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response

The tumor microenvironment (TME) is a challenging environment where cells must cope with stressful conditions such as fluctuating pH levels, hypoxia, and free radicals. In response, stress pathways are activated, which can both promote and inhibit tumorigenesis. In this study, we set out to characterize the stress response landscape across four carcinomas: breast, pancreas, ovary, and prostate tumors, focusing on five pathways: Heat shock response, oxidative stress response, unfolded protein response, hypoxia stress response, and DNA damage response. Using a combination of experimental and computational methods, we create an atlas of the stress response landscape across various types of carcinomas. We find that stress responses are heterogeneously activated in the TME, and highly activated near cancer cells. Focusing on the non-immune stroma we find, across tumor types, that NRF2 and the oxidative stress response are distinctly activated in immune-regulatory cancer-associated fibroblasts and in a unique subset of cancer associated pericytes. Our study thus provides an interactome of stress responses in cancer, offering new ways to intersect survival pathways within the tumor, and advance cancer therapy.

cancer biology↗

bioRxiv2022

Clonal evolution during metastatic spread in high-risk neuroblastoma

High-risk neuroblastoma is generally metastatic and often lethal. Using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis, through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.

genomics↗

bioRxiv2018

The mutational landscape of normal human endometrial epithelium

All normal somatic cells are thought to acquire mutations. However, characterisation of the patterns and consequences of somatic mutation in normal tissues is limited. Uterine endometrium is a dynamic tissue that undergoes cyclical shedding and reconstitution and is lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands showed that most are clonal cell populations derived from a recent common ancestor with mutation burdens differing from other normal cell types and manyfold lower than endometrial cancers. Mutational signatures found ubiquitously account for most mutations. Many, in some women potentially all, endometrial glands are colonised by cell clones carrying driver mutations in cancer genes, often with multiple drivers. Total and driver mutation burdens increase with age but are also influenced by other factors including body mass index and parity. Clones with drivers often originate during early decades of life. The somatic mutational landscapes of normal cells differ between cell types and are revealing the procession of neoplastic change leading to cancer.

cancer biology↗