Biology subjects

Engelholm, L. H.

Publications and source records attributed to Engelholm, L. H..

4 recordsLinked to original sources

bioRxiv2026

Acquired resistance to immune checkpoint inhibitors is associated with hypoxia and ECM remodeling in colorectal cancer

Acquired resistance to immune checkpoint inhibitors (ICIs) limits the durability of therapeutic responses across multiple cancer types, yet the underlying mechanisms remain poorly defined. Using the murine MC38 colorectal cancer model, we established an in vivo model recapitulating clinical response patterns, including complete regression, primary resistance, and acquired resistance. Tumors with acquired resistance progressed after initial benefit from combined anti-PD-1 and anti-CTLA-4 therapy and maintained resistance upon retransplantation into naive hosts, indicating a cancer cell-intrinsic driver of resistance. Whole-genome sequencing showed no mutations in antigen presentation or IFN-{gamma} signaling pathways previously described in single clinical cases of acquired resistance, and functional assays confirmed preserved antigenicity and IFN-{gamma} responsiveness. Transcriptomic and metabolic profiling of resistant cancer cells instead revealed metabolic reprogramming characterized by enhanced mitochondrial respiration and enrichment of hypoxia-related gene signatures, suggesting cancer cell-intrinsic adaptations that reshape the tumor microenvironment. Tumors with acquired resistance exhibited an increase in tumor-associated macrophages, and these macrophages displayed enriched transcriptional signatures of hypoxia, angiogenesis, and extracellular matrix (ECM) remodeling. Proteomic analysis of ECM-enriched tumor fragments showed accumulation of proteoglycans and enzymes such as lysyl oxidase, consistent with active matrix-remodeling. These changes coincided with altered T cell activation characterized by reduced cytotoxic gene expression and decreased CD44 expression on tumor-infiltrating T cells, suggesting impaired effector functions within the resistant microenvironment. This study identifies non-genetic mechanisms of acquired resistance to ICIs and highlights metabolic and ECM remodeling programs as promising therapeutic targets to prevent or reverse acquired resistance to ICIs.

cancer biology↗

bioRxiv2026

Collagen type I promotes pancreatic tumor growth and limits immune cell infiltration

Solid tumors are often characterized by a dense extracellular matrix (ECM) that contributes to increased tissue stiffness. Collagen type I is the main component of the ECM and its abundance in tumors is frequently associated with poor prognosis. In vitro studies suggest that a high collagen density promotes tumor invasion and modulates immune responses. However, recent in vivo findings have questioned the pro-tumorigenic role of collagen type I. In this study, we investigate the role of collagen for pancreatic tumor growth and immune cell infiltration using conditional collagen type I knockout mice and transgenic collagenase-resistant mice. Preventing collagen type I significantly reduces intratumoral collagen content and tumor growth. This reduction is accompanied increased infiltration of natural killer (NK) cells, a higher CD8/CD4 T cell ratio, and decreased numbers of monocytic myeloid-derived suppressor cells (MDSCs). Conversely, collagenase-resistant mice develop collagen-dense tumors and display enhanced tumor growth. These mice also generally exhibit opposing effects on cell infiltration, including a lower CD8/CD4 ratio and increased MDSC abundance. These findings are further supported by analyses of publicly available human cancer datasets, which confirm an association between collagen type I levels and immune cell infiltration. Overall, our results demonstrate a pronounced pro-tumorigenic role of collagen type I in pancreatic cancer, which is associated with modulation of the tumor immune microenvironment. This study highlights the importance of extracellular matrix components as key regulators of tumor progression and anti-tumor immunity.

cancer biology↗

bioRxiv2022

A platform for efficient establishment, expansion and drug response profiling of high-grade serous ovarian cancer organoids

The broad research use of organoids from high-grade serous ovarian carcinoma (HGSC) has been hampered by low culture success rates and limited availability of fresh tumor material. Here we describe a method for generation and long-term expansion of HGSC organoids with efficacy markedly improved over previous reports (55% vs. 23-38%). We established organoids from cryopreserved material, demonstrating the feasibility of using viably biobanked tissue for HGSC organoid derivation. Genomic, histologic and single-cell transcriptomic analyses revealed that organoids recapitulated genetic and phenotypic features of original tumors. Organoid drug responses correlated with clinical treatment outcomes, although in culture conditions-dependent manner and only in organoids maintained in human plasma-like medium (HPLM). Organoids from consenting patients are available to the research community through a public biobank and organoid genomic data explorable through an interactive online tool. Taken together, this resource facilitates the application of HGSC organoids in basic and translational ovarian cancer research.

cancer biology↗

bioRxiv2018

Collagen density regulates the activity of tumor-infiltrating T cells

BackgroundTumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.\n\nMethodsT cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.\n\nResultsT cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer.\n\nWhole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-B signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.\n\nConclusionsOur study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.

immunology↗