Immunology
Abstract
While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of cancer patients. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet the molecular mechanisms underlying impaired MHC-I remain to be fully elucidated. Herein, we identified USP22 as a critical factor responsible for ICB resistance through suppressing MHC-I-mediated neoantigen presentation to CD8 T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcome anti-PD-1 immunotherapeutic resistance. At the molecular level, USP22 functions as a deubiquitinase for the methyltransferase EZH2, leading to transcriptional silencing of MHC-I gene expression. Targeted Usp22 inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8 T cell killing, which was largely abrogated by Ezh2 reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both 2M expression and CD8+ T lymphocyte infiltration in solid tumors. Importantly, USP22 upregulation was associated with ICB immunotherapeutic resistance in patients with lung cancer. Collectively, this study highlights the role of USP22 as a diagnostic biomarker for ICB resistance and provides a potential therapeutic avenue to overcome the current ICB resistance through inhibition of USP22.
Authors
Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang
Abstract
Intestinal function and white adipose tissue (WAT) function deteriorate with age, but whether and how their deterioration is intertwined remains unknown. Increased gut permeability, microbiota dysbiosis, and aberrant immune microenvironment are the hallmarks of intestinal dysfunctions in aging. Here, we show that subcutaneous WAT dysfunction triggered aging-like intestinal dysfunctions in mouse models. Removal of inguinal subcutaneous WAT (iWAT) increased intestinal permeability and inflammation and altered gut microbiota composition as well as susceptibility to pathogen infection in mouse models. These intestinal dysfunctions were accompanied by a reduction of immunoglobulin A–producing (IgA-producing) cells and IgA biosynthesis in the lamina propria of the small intestine. Retinoic acid (RA) is a key cargo within iWAT-derived extracellular vesicles (iWAT-EVs), which, at least in part, elicits IgA class-switching and production in the small intestine and maintains microbiota homeostasis. RA content in iWAT-EVs and intestinal IgA biosynthesis are reduced during aging in mice. Replenishment of “young” iWAT-EVs rejuvenates intestinal IgA production machinery and shifts microbiota composition of aged mice to a “youth” status, which alleviates leaky gut via RA. In conclusion, our findings suggest that iWAT-EVs with RA orchestrate IgA-mediated gut microbiota homeostasis by acting on intestinal B cells, thereby maintaining intestinal health during aging.
Authors
KeKao Long, Pujie Liu, Yi Wang, Jordy Evan Sulaiman, Moinul Hoque, Gloria Hoi Yee Li, Daisy Danyue Zhao, Pui-Kei Lee, Gilman Kit-hang Siu, Annie Wing-tung Lee, Zhuohao Liu, Pui-kin So, Yin Cai, Connie Wai-hong Woo, Chi-bun Chan, Aimin Xu, Kenneth King-yip Cheng
Abstract
Influenza and other respiratory viral pathogens remain leading causes of mortality and morbidity. Circadian rhythms play a critical role in regulating immune responses and can confer temporal protection from influenza infection. Here, we investigated whether this protection requires rhythmic function after the initial infection by manipulating environmental cycles. We found that disrupting environmental lighting cues within a critical window of vulnerability abrogated the time-of-day-specific protection. This poor outcome was mediated by a dysregulated immune response, as evidenced by the accumulation of inflammatory monocytes and CD8+ T cells in the lungs and a transcriptomic profile indicative of an exaggerated inflammation. Disruption of the light cycle did not affect outcomes in a clock mutant, indicating that it acts through the host’s circadian clock. Importantly, rhythmic meal timing mitigated the adverse effects of disrupted light cycles, supporting the idea that external cues acting through different body clocks can compensate for one another. Together, these findings underscore the critical interplay between environmental timing cues and endogenous circadian rhythms in determining influenza outcomes and offer translational insight into optimizing care for critically ill patients with respiratory viral infections.
Authors
Oindrila Paul, Thomas G. Brooks, Alisha Shetty, Y. Jane Choi, Martina Towers, Lora J. Assi, James P. Garifallou, Kaitlyn Forrest, Alecia Cameron, Amita Sehgal, Gregory Grant, Shaon Sengupta
Abstract
Macrophage-mediated phagocytosis plays a critical role in the elimination of cancer cells and shaping antitumor immunity. However, the tumor-intrinsic pathways that regulate cancer cell sensitivity to macrophage-mediated phagocytosis remain poorly defined. In this study, we performed a genome-wide CRISPR screen in murine pancreatic cancer cells cocultured with primary macrophages and identified that disruption of the tumor-intrinsic pyrimidine synthesis pathway enhances phagocytosis. Mechanistically, we discovered that macrophages inhibit the pyrimidine salvage pathway in tumor cells by upregulating Upp1-mediated uridine degradation through cytokines TNF-α and IL-1. This shift increased tumor cells’ reliance on de novo pyrimidine synthesis. As a result, tumor cells with impaired de novo pyrimidine synthesis showed depleted UMP and displayed enhanced exposure of phosphatidylserine (PtdSer), a major “eat-me” signal, thereby promoting macrophage-mediated phagocytosis. In multiple pancreatic cancer models, Cad-deficient tumors exhibited markedly reduced tumor burden with increased levels of phagocytosis by macrophages. Importantly, the Cad-mediated suppression of pancreatic cancer was dependent on TAMs and cytokines IL-1 and TNF-α. Pharmacological inhibition of DHODH, which blocks de novo pyrimidine synthesis, similarly decreased tumor burden with enhanced phagocytosis in pancreatic cancer models. These findings highlight the critical role of the tumor-intrinsic pyrimidine synthesis pathway in modulating macrophage-mediated antitumor immunity, with potential therapeutic implications.
Authors
Jie Zhao, Xinghao Li, Xinyu Li, Pengfei Ren, Yilan Wu, Hao Gong, Lijian Wu, Junran Huang, Saisai Wang, Ziwei Guo, Mo Chen, Zexian Zeng, Deng Pan
Abstract
A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of mortality after lung transplantation (LTx), is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early post-lung transplantation to form the C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3R102G) that increases complement activation through impaired C3 convertase inactivation in two independent LTx recipient cohorts. C3R102G, identified in at least one out of three LTx recipients, was associated with worse CLAD-free survival, particularly in the subset of recipients who developed donor-specific antibodies (DSAs). In a mouse orthotopic lung transplant model, impaired recipient complement regulation led to B cell-dependent CLAD pathology despite moderate differences in graft-infiltrating effector T cells. Dysregulated complement regulation promoted intragraft accumulation of memory B cells and antibody-secreting cells, leading to increased local and circulating DSA levels in mice. In summary, genetic predisposition to complement activation is associated with an increased humoral response and worse CLAD-free survival.
Authors
Hrishikesh S. Kulkarni, Laneshia K. Tague, Daniel R. Calabrese, Fuyi Liao, Zhiyi Liu, Lorena Garnica, Nishanth R. Shankar, Xiaobo Wu, Devesha H. Kulkarni, Aayusha Thapa, Dequan Zhou, Yan Tao, Victoria E. Davis, Cory T. Bernadt, Derek E. Byers, Catherine Chen, Howard J. Huang, Chad A. Witt, Ramsey R. Hachem, Daniel Kreisel, John P. Atkinson, John R. Greenland, Andrew E. Gelman
Abstract
Authors
Jarne Beliën, Amber De Visscher, Bethany Pillay, Marjon Wouters, Verena Kienapfel, Eline Bernaerts, Tania Mitera, Nele Berghmans, Bénédicte Dubois, Leen Moens, Patrick Matthys, Isabelle Meyts
Abstract
Authors
Kristy Tefft, Amy Wang, Zachary Z. Reinstein, Yue Zhang, Arundhati Pillai, Sunghee Hwang, Spencer Ng, Raymond J. Cho, Jeffrey B. Cheng, Fei Li Kuang, Brett King, Jaehyuk Choi
Abstract
CAR-T therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematological toxicity (ICAHT). We utilized IL-2Rα knockout mice to model toxicities with elevated levels of IL6, IFNγ, and TNFα and increased M1-like macrophages. Onset of CRS was accompanied by a reduction in peripheral blood neutrophils due to disruption of bone marrow neutrophil homeostasis characterized by an increase in apoptotic neutrophils and a decrease in proliferative and mature neutrophils. Both non-tumor-bearing and Eμ-ALL tumor-bearing mice recapitulated the co-occurrence of CRS and neutropenia. IFNγ-blockade alleviated CRS and neutropenia without affecting CAR-T efficacy. Mechanistically, a Th1-Th17 imbalance was observed to drive co-occurrence of CRS and neutropenia in an IFNγ-dependent manner leading to decreased IL-17A and G-CSF, neutrophil production, and neutrophil survival. In patients, we observed an increase in the IFNγ-to-IL-17A ratio in the peripheral blood during high-grade CRS and neutropenia. We have uncovered a biological basis for ICAHT and provide support for the use of IFNγ-blockade to reduce both CRS and neutropenia.
Authors
Payal Goala, Yongliang Zhang, Nolan J. Beatty, Allan Pavy, Shannon L. McSain, Cooper J. Sailer, Muhammad Junaid Tariq, Showkat Hamid, Eduardo Cortes Gomez, Jianmin Wang, Duna Massillon, Maxwell Ilecki, Justin C. Boucher, Constanza Savid-Frontera, Sae Bom Lee, Hiroshi Kotani, Meredith L. Stone, Michael D. Jain, Marco L. Davila
Abstract
Liver metastases are relatively resistant to checkpoint blockade immunotherapy. The hepatic tissue has distinctive features including high numbers of NK cells. It was therefore important to conduct in depth single-cell analysis of NK cells in colorectal cancer liver metastases (CRLMs) with the effort to dissect their diversity and to identify candidate therapeutic targets. By combining unbiased single-cell transcriptomic with multiparametric flow cytometry analysis, we identified an abundant family of intrahepatic CD56Bright NK cells in CRLMs endowed with anti-tumor functions resulting from specific transcriptional liver programs. Intrahepatic CD56Bright and CD56Dim NK lymphocytes expressed unique transcription factors (IRF8, TOX2), high level of chemokines, and targetable immune checkpoints (ICs), including CXCR4 and the IL-1 receptor family member IL-1R8. CXCR4 pharmacological blocking and an anti-IL-1R8 mAb enhanced the effector function of CRLM NK cells. Targeting the diversity of liver NK cells and their distinct immune-checkpoint repertoires is key to optimize the current immune-therapy protocols in CRLM.
Authors
Joanna Mikulak, Domenico Supino, Paolo Marzano, Sara Terzoli, Roberta Carriero, Valentina Cazzetta, Rocco Piazza, Elena Bruni, Paolo Kunderfranco, Alessia Donato, Sarah Natalia Mapelli, Roberto Garuti, Silvia Carnevale, Francesco Scavello, Elena Magrini, Jelena Zeleznjak, Clelia Peano, Matteo Donadon, Guido Costa, Guido Torzilli, Alberto Mantovani, Cecilia Garlanda, Domenico Mavilio
Abstract
Harnessing the stimulator of interferon genes (STING) signaling pathway to trigger innate immune responses has shown remarkable promise in cancer immunotherapy; however, overwhelming resistance to intratumoral STING monotherapy has been witnessed in clinical trials, and the underlying mechanisms remain to be fully explored. Herein, we show that pharmacological STING activation following the intratumoral injection of a non-nucleotide STING agonist (i.e., MSA-2) results in apoptosis of the cytolytic T cells, interferon-mediated overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), and evasion from immune surveillance. We leverage a noncovalent chemical strategy for developing immunomodulatory binary nanoparticles (iBINP) that include both the STING agonist and an IDO1 inhibitor for treating immune-evasive tumors. This iBINP platform developed by dual prodrug engineering and subsequent nanoparticle assembly enables tumor-restricted STING activation and IDO1 inhibition, achieving immune activation while mitigating immune tolerance. A systemic treatment of preclinical models of colorectal cancer with iBINP resulted in robust antitumor immune responses, reduced infiltration of regulatory T cells, and enhanced activity of CD8+ T cells. Importantly, this platform exhibits great therapeutic efficacy by overcoming STING–induced immune evasion and controlling the progression of multiple tumor models. This study unveils the mechanisms by which STING monotherapy induces immunosuppression in the tumor microenvironment and provides a combinatorial strategy for advancing cancer immunotherapies.
Authors
Fanchao Meng, Hengyan Zhu, Shuo Wu, Bohan Li, Xiaona Chen, Hangxiang Wang
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)