Biology subjects

Snyder, C. M.

Publications and source records attributed to Snyder, C. 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

NF-kB-Dependent Transcriptional Regulation of Piezo1 Mediates Bacterial Clearance on Stiffened Lung

Respiratory pathogens, such as Pseudomonas aeruginosa damage the alveolar-capillary barrier leading to lung injury and stiffness. Lung stiffness is a key macrophage signal for bacterial clearance, but it remains unknown how stiffness-sensing mechanosensitive ion channels in macrophages are regulated during pneumonia. Macrophage Piezo1 is critical to bacterial clearance in experimental pneumonia in vivo; however, identification of putative matrix-derived signals and the mechanism of their effects remain to be determined. To our knowledge, our work is the first to show that during pneumonia, transcription of the mechanosensitive ion channel Piezo1 is increased in macrophages by the NF-{kappa}B transcription factor, p65, through its signaling adaptor protein, MyD88, leading to increased Piezo1 Ca2+ channel activity. Piezo1 mRNA abundance is increased in association with open chromatin at the Piezo1 promoter in macrophages. The enhanced level of Piezo1 increases the abundance of transcription factor EB (Tfeb) resulting in lysosome biogenesis and stiffness-dependent phagolysosome maturation, a critical step for macrophage bacterial clearance. Our data support the mechanism whereby transcription of macrophage Piezo1 is enhanced by p65 to augment bacterial clearance on an injured, stiffened lung matrix during pneumonia. Therefore, Piezo1 is a future therapeutic target against pneumonia-induced lung injury.

immunology↗

bioRxiv2019

NK cells force cytomegalovirus to use hematopoietic cells and immune evasion for dissemination after mucosal infection

Cytomegalovirus (CMV) infects most people in the world and causes clinically important disease in immune compromised and immune immature individuals. How the virus disseminates from the initial site of infection is poorly understood. We used an innovative approach, involving insertion of target sites for the haematopoietic specific miRNA miR-142-3p into an essential viral gene in murine cytomegalovirus. This virus was unable to disseminate to the salivary gland following intranasal infection, demonstrating a strict need for hematopoietic cells for dissemination from the natural site of infection. Viral immune evasion genes that modulate MHC-I expression and NKG2D activation were also required in this setting, as MCMV lacking these genes exhibited impaired dissemination of the viral genome to the salivary gland, and there was no detectable viral replication in the salivary gland. Depletion of T cells rescued the replication of this evasion-deficient virus in the salivary gland. Surprisingly however, the early dissemination to the salivary gland of this evasion-deficient virus, could be rescued by depletion of NK cells, but not T cells. These data are the first to show a profound loss of MCMV fitness in the absence of its MHC-I evasion genes and suggest that they protect the virus from NK cells during hematopoietic dissemination to the salivary gland, where they continued to need the three evasion genes to avoid T cell responses. Remarkably, we found that depletion of NK cells also freed the virus from the need to infect hematopoietic cells in order to reach the salivary gland. Thus, our data show that MCMV adapts to NK cell pressure after intranasal infection by using hematopoietic cells for dissemination while immune evasion genes protect the virus from NK cells during dissemination and from T cells within mucosal tissues.

immunology↗

bioRxiv2019

Murine cytomegalovirus infection of melanoma lesions delays tumor growth by recruiting and re-polarizing monocytic phagocytes in the tumor

Cytomegalovirus (CMV) is a ubiquitous {beta}-herpesvirus that infects many different cell types. CMV has been found in several solid tumors and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, CMV infection delays tumor growth. We previously showed that wild-type murine (M)CMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here we show that MCMV delayed the growth of these immunologically \"cold\" tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward an M1-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the anti-tumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically \"cold\" tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses.\n\nImportanceCytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine (M)CMV delayed tumor growth and activated tumor-specific immunity, although the mechanism was unclear. We now show that MCMV delayed tumor growth not by infecting and killing tumor cells, but rather by recruiting macrophages to the tumor. A viral chemokine was necessary to recruit macrophages and delay tumor growth. Furthermore, MCMV infection altered the functional state of the macrophages. Finally, we found that repeated MCMV injections sustained the anti-tumor effect suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting and infecting macrophages in the tumor.

immunology↗