Immunology
Abstract
Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita–/– and H2-Ab1–/– ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.
Authors
Vera Tiedje, Jillian Greenberg, Tianyue Qin, Soo-Yeon Im, Gnana P. Krishnamoorthy, Laura Boucai, Bin Xu, Jena D. French, Eric J. Sherman, Alan L. Ho, Elisa de Stanchina, Nicholas D. Socci, Jian Jin, Ronald A. Ghossein, Jeffrey A. Knauf, Richard P. Koche, James A. Fagin
Abstract
Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin disorder characterized by erythematous plaques with a dense dermal neutrophilic infiltrate. First-line therapy remains oral corticosteroids, which suppresses inflammation non-specifically. Although neutrophils are typically short-lived, how they persist in Sweet syndrome skin and contribute to disease pathogenesis remains unclear. Here, we identify a previously unrecognized population of antigen-presenting cell (APC)-like neutrophils expressing MHC class II genes that are uniquely present in Sweet syndrome skin but absent from healthy tissue and circulation. Keratinocytes extended neutrophil lifespan 10-fold in co-culture experiments and drove the emergence of an APC-like phenotype in approximately 30% of neutrophils, mirroring observations in patient lesions. Mechanistically, keratinocyte-derived serum amyloid A1 (SAA1) signals through the formyl peptide receptor 2 (FPR2) on neutrophils to promote their survival. These long-lived neutrophils actively orchestrate local immune responses by recruiting T cells and inducing cytokine production. Strikingly, dual blockade of SAA1-FPR2 signaling restores neutrophil turnover to baseline levels, with efficacy comparable to high-dose corticosteroids. These findings uncover a keratinocyte-neutrophil-T cell axis that sustains chronic inflammation in Sweet syndrome and highlight the SAA1/FPR2 pathway as a promising target for precision therapy.
Authors
Jianhe Huang, Satish Sati, Olivia Ahart, Emmanuel Rapp-Reyes, Linda Zhou, Robert G. Micheletti, William D. James, Misha Rosenbach, Thomas H. Leung
Abstract
Crypt hyperplasia is a key feature of celiac disease and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry-based tissue proteomics revealed a strong interferon-γ (IFN-γ) signal in active celiac disease. This signal, hallmarked by increased expression of MHC molecules, was paralleled by diminished expression of proteins associated with fatty acid metabolism. Crypt hyperplasia and the same proteomic changes were observed in wild type mice administered IFN-γ. In mice with conditional knockout of the IFN-γ receptor in gut epithelial cells these signature morphological and proteomic changes were not induced on IFN-γ administration. IFN-γ is thus a driver of crypt hyperplasia in celiac disease by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-γ.
Authors
Jorunn Stamnaes, Daniel Stray, M. Fleur du Pré, Louise F. Risnes, Alisa E. Dewan, Jakeer Shaik, Maria Stensland, Knut E.A. Lundin, Ludvig M. Sollid
Abstract
Authors
Alireza Raissadati, Xuanyu Zhou, Harrison Chou, Yuhsin Vivian Huang, Shaheen Khatua, Yin Sun, Anne Xu, Sharon Loa, Arturo Hernandez, Han Zhu, Sean M. Wu
Abstract
Toll like receptor (TLR) 7 and 9, endosomal sensors for RNA and DNA, are key mediators of autoreactivity. Although generally considered homologous, they paradoxically have opposing effects on lupus: TLR7 exacerbates disease while TLR9 protects from disease. How they mediate opposing effects in autoimmunity remains undetermined. We hypothesized that differences in signaling qualities of the Toll-Interleukin 1 Receptor (TIR) domains of TLR7 and TLR9 could be responsible for their opposing effects. To test this, we introduced the TIR domain of TLR9 into the endogenous TLR7 locus and the TLR7 TIR domain into the endogenous TLR9 locus of mice, creating chimeric molecules termed TLR779 and TLR997. Lupus-prone MRL/lpr mice carrying Tlr779 had greatly ameliorated disease while MRL/lpr mice carrying Tlr997 had markedly exacerbated disease compared to respective TlrWT mice. These experiments establish that TLR7 and TLR9 TIR domains have divergent properties and control disease quality, thus explaining the longstanding “TLR paradox.”
Authors
Claire Leibler, Kayla B. Thomas, Coralie Josensi, Russell C. Levack, Shuchi Smita, Shinu John, Daniel J. Wikenheiser, Sheldon Bastacky, Sebastien Gingras, Kevin M. Nickerson, Mark J. Shlomchik
Abstract
Through a combination of single-cell/single-nucleus RNA-sequencing (sc/snRNA-seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by TET3 overexpression (Toe-Macs) in three major human diseases associated with chronic inflammation: metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enables their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 knockout markedly mitigates disease progression and the therapeutic effects are recapitulated pharmacologically using a TET3-specific small molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulates expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.
Authors
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia V. Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
Abstract
Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung.
Authors
Yahui Guo, Mariano A. Aufiero, Kathleen A.M. Mills, Simon A. Grassmann, Hyunu Kim, Mergim Gjonbalaj, Paul Zumbo, Audrey Billips, Katrina B. Mar, Yao Yu, Laura Echeverri Tirado, Lena Heung, Amariliz Rivera, Doron Betel, Joseph C. Sun, Tobias M. Hohl
Abstract
BRD4 is an epigenetic reader protein that regulates oncogenes such as myc in cancer. However, its additional role in shaping immune responses via regulation of inflammatory and myeloid cell responses is not yet fully understood. This work further characterized the multifaceted role of BRD4 in anti-tumor immunity. NanoString gene expression analysis of EMT6 tumors treated with a BRD4 inhibitor identified a reduction in myeloid gene expression signatures. Additionally, BRD4 inhibition significantly reduced myeloid derived suppressor cells (MDSC) in the spleens and tumors of mice in multiple tumor models and also decreased the release of tumor-derived MDSC growth and chemotactic factors. Pharmacologic inhibition of BRD4 in MDSC induced apoptosis and modulated expression of apoptosis regulatory proteins. A BRD4-myeloid specific knockout model suggested that the dominant mechanism of MDSC reduction after BRD4 inhibition was primarily through a direct effect on MDSC. BRD4 inhibition enhanced anti-PD-L1 therapy in the EMT6, 4T1, and LLC tumor models, and the efficacy of the combination treatment was dependent on CD8+ T cells and on BRD4 expression in the myeloid compartment. These results identify BRD4 as a regulator of MDSC survival and provide evidence to further investigate BRD4 inhibitors in combination with immune based therapies.
Authors
Himanshu Savardekar, Andrew Stiff, Alvin Liu, Robert Wesolowski, Emily Schwarz, Ian C. Garbarine, Megan C. Duggan, Sara Zelinskas, Jianying Li, Gabriella Lapurga, Alexander Abreo, Lohith Savardekar, Ryan Parker, Julia Sabella, Mallory J. DiVincenzo, Brooke Benner, Steven H. Sun, Dionisia Quiroga, Luke Scarberry, Gang Xin, Anup Dey, Keiko Ozato, Lianbo Yu, Merve Hasanov, Debasish Sundi, Richard C. Wu, Kari L. Kendra, William E. Carson III
Abstract
Gasdermin (GSDM) family proteins mediate tumor pyroptosis and impact cancer progression, but other than that, their involvement in the tumor immune microenvironment remains largely unknown. Here, we show that activation of GSDMD in human tumor specimens mainly occurs in tumor-infiltrating leukocytes. Significantly, GSDMD deficiency or its inactivation in CD4+ T cells disabled CD8+ T cell–mediated antitumor immunity and caused tumor outgrowth in mice. Further study uncovered that, via inducing IL-2 production, GSDMD was required for CD4+ T cells to provide help to CD8+ T cell function. Mechanistically, GSDMD was cleaved by TCR stimulation–activated caspase-8 to form GSDMD-N pores, which enhanced Ca2+ influx for IL-2 induction. Moreover, GSDMD activation and function were conserved in human CD4+ T cells and associated with favorable prognosis and improved response to anti–PD-1 immunotherapy in colonic and pancreatic cancer. We believe this study identifies a new nonpyroptotic role of GSDMD in tumor immunity, proposing GSDMD as a potential target for cancer immunotherapy.
Authors
Yihan Yao, Lingling Wang, Weiqin Jiang, Ning Wang, Mengjie Li, Wenlong Lin, Ting Zhang, Wanqiang Sheng, Xiaojian Wang
Abstract
Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β cells, resulting in permanent loss of glucose homeostasis. Islet transplantation is a promising potential cure that remains hindered by immune rejection. We previously showed that ST8Sia6 expression on tumors reduced immune surveillance and hypothesized that this sialyltransferase could protect β cells from autoimmune destruction. Here, we demonstrate that ectopic expression of ST8Sia6 in β cells of female nonobese diabetic mice (NOD βST) decreased the spontaneous incidence of diabetes by 90% and preserved β cell mass. NOD βST mice had comparable insulitis at 8 weeks of age that did not progress over time compared with littermate controls. β Cell–autoreactive B and T cells were present in NOD βST mice, indicating a peripheral rather than central mechanism of immune tolerance. The islets of NOD βST mice displayed a dampened type 1 immune response and reduced IL-12p35 expression in dendritic cells compared with those of littermate controls. The peripheral protection persisted even after removal of ST8Sia6 expression at 20 weeks of age, indicating that transient expression was sufficient for establishment of tolerance. These results demonstrate that ST8Sia6 protects β cells from immune-mediated attack and rejection, highlighting its therapeutic potential for autoimmune disorders.
Authors
Justin Choe, Paul Belmonte, Sydney Crotts, Thanh Nguyen, David Friedman, Alexi Zastrow, Matthew Rajcula, Brady Hammer, Claire Wilhelm, Michael J. Shapiro, Aleksey Matveyenko, Virginia Smith Shapiro
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)