Biology subjects

Yu, K. H.

Publications and source records attributed to Yu, K. H..

3 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↗

bioRxiv2020

DETECTION OF INCIPIENT PANCREATIC CANCER WITH NOVEL TUMOR-SPECIFIC ANTIBODIES IN MOUSE MODELS

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, as 90% of patients do not survive beyond five years from diagnosis. This dismal prognosis is largely due to the advanced stage of the disease at diagnosis, which precludes potentially curative surgical resection. Although early detection strategies hold significant promise for improving patient outcomes, there is still no accurate diagnostic tool to detect incipient PDAC. Here, we sought to develop antibodies for the early detection of PDAC by positron-emission tomography (PET) imaging. Accordingly, we establish a pipeline to generate novel tumor-specific monoclonal antibodies (mAbs) against cell-surface proteins of PDAC patient-derived organoids (PDOs). We identify a panel of 16 tumor organoid-binding antibodies (TOBi-bodies) that display high reactivity to human PDAC tissues but not to matched adjacent normal pancreas. We then employ biochemical, flow cytometric, mass spectrometric, and CRISPR/Cas9-mediated knockout methods to determine the cognate antigens of these TOBi-bodies. We identify two mAbs that bind to tumor-specific variants of the surface protein CEACAM6 and show minimal binding to normal tissues. PET imaging in mouse models using these TOBi-bodies enables the detection of incipient human organoid-derived PDAC tumors that are rather undetectable by palpation or high-resolution ultrasound imaging techniques. We propose that further development of these mAbs as PET radiotracers could facilitate the early detection and accurate staging of PDAC.

cancer biology↗