Biology subjects

Sadow, P. M.

Publications and source records attributed to Sadow, P. M..

4 recordsLinked to original sources

bioRxiv2025

Antibody peptide epitope conjugates for αPD-1 therapy-resistant head and neck squamous cell carcinoma

Poor tumor antigenicity is an important cause of non-response to immune checkpoint blockade (ICB)-therapy in many cancer patients and mandates new treatment strategies. Here we explore the use of proteolytically activated antibody-peptide epitope conjugates (APECs) to redirect the immunological effector activities of tumor-infiltrating antiviral bystander CTLs against head and neck squamous cell carcinoma (HNSCC) by loading cancer cell surface MHC I proteins with viral peptides. We find that inflationary T cell memory responses against common viral pathogens such as CMV and EBV unfold superior anti-tumor activity compared to conventional memory responses under APEC therapy in an ICB-resistant preclinical model of HNSCC. Mechanistically, APEC activation required cancer cell-intrinsic protease activity, even for proteases expressed by cells of the tumor stroma. Data mining and functional screening identified the protease activity of plasminogen activator urokinase (PLAU) as widely shared between human HNSCC cancers and as a highly efficient proteolytic activator of APECs. Furthermore, peripheral blood analysis in HNSCC patients reliably predicts the specificity, magnitude, and quality of intratumoral bystander CTL, thus allowing for the screening of HNSCC patients who may benefit most from APEC therapy.

immunology↗

bioRxiv2025

Immune-parenchymal multicellular niches are shared across distinct thyroid autoimmune diseases

Thyroid hormone, produced in the thyroid gland, regulates metabolism, development, and cardiac function. The thyroid is susceptible to autoimmune attack by both cellular and humoral immunity exemplified by Hashimotos thyroiditis (HT) and Graves Disease (GD), respectively. In HT, immune-mediated destruction impairs thyroid hormone production, while in GD, stimulating autoantibodies promote over-production. Here, we generated a multi-modal atlas of 604,076 human thyroid and blood cells from HT, GD, and control patients. We found that, despite markedly different clinical presentations and distinct antigenic triggers, HT and GD exhibit convergent cellular dynamics resulting in a shared continuum of immune infiltration. Along this continuum, a key feature is a thyrocyte niche containing CD8+ T cells that may segregate pathogenic T cells from regions with preserved thyroid hormone production. These findings of a shared disease continuum characterized by spatially defined immune niches provide a new framework for understanding tissue homeostasis in human autoimmune disease.

immunology↗

bioRxiv2024

Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma

PurposeAdenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental DesignWe leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-{psi} or a STING agonist. ResultsmIF demonstrated that ACC tumors are immunologically cold, with few tumor- infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-{psi} or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. ConclusionsLow/absent HLA/B2M expression may explain ACC tumors immunologically cold status and lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.

cancer biology↗

bioRxiv2022

Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma

Oncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging, a safeguard against ferroptosis, to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SignificanceOncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is a unique tumor with a remarkable accumulation of mitochondria. HCC harbors unique genetic alterations, including mitochondrial DNA (mtDNA) mutations in complex I genes and widespread loss-of-heterozygosity in the nuclear DNA. With less favorable clinical outcomes, new therapies for HCC are needed, especially since these tumors show intrinsic resistance to radioactive iodine, which is one of the main treatments for metastatic well-differentiated thyroid cancer. An absence of authentic HCC cell lines and animal models has hindered the mechanistic understanding of this disease and slowed therapeutic progress. In this study, we describe the transcriptomic and metabolomic landscape of HCC and present new HCC models that recapitulate key mtDNA and nuclear DNA alterations. A targeted CRISPR-Cas9 knockout screen in an HCC cell line highlights the molecular programs nominated by our -omics profiling that are required for cell fitness. This screen suggests that lipid peroxide scavenging, a defense system against an iron-dependent form of cell death known as ferroptosis, is a vulnerability in HCC that is coupled to complex I loss, and that targeting this pathway may help patients with HCC.

cancer biology↗