Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adu0983
Jonathan S. Maltzman
OX40L–CAR-Tregs show promise for treating autoimmunity and transplantation rejection.
OX40L-CAR-Tregs有望治疗自身免疫和移植排斥反应。
{"title":"CAR-ving away OX40L with engineered Tregs","authors":"Jonathan S. Maltzman","doi":"10.1126/sciimmunol.adu0983","DOIUrl":"10.1126/sciimmunol.adu0983","url":null,"abstract":"<div >OX40L–CAR-T<sub>regs</sub> show promise for treating autoimmunity and transplantation rejection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adn2168
Gerone A. Gonzales, Song Huang, Liam Wilkinson, Jenny A. Nguyen, Saif Sikdar, Cécile Piot, Victor Naumenko, Jahanara Rajwani, Cassandra M. Wood, Irene Dinh, Melanie Moore, Eymi Cedeño, Neil McKenna, Maria J. Polyak, Sara Amidian, Vincent Ebacher, Nicole L. Rosin, Matheus B. Carneiro, Bas Surewaard, Nathan C. Peters, Christopher H. Mody, Jeff Biernaskie, Robin M. Yates, Douglas J. Mahoney, Johnathan Canton
Conventional dendritic cells (cDCs) generate protective cytotoxic T lymphocyte (CTL) responses against extracellular pathogens and tumors. This is achieved through a process known as cross-presentation (XP), and, despite its biological importance, the mechanism(s) driving XP remains unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein L 7C (APOL7C) is up-regulated in response to innate immune stimuli and is recruited to phagosomes. Association of APOL7C with phagosomes led to phagosomal rupture and escape of engulfed antigens to the cytosol, where they could be processed via the endogenous MHC class I antigen processing pathway. Accordingly, mice deficient in APOL7C did not efficiently prime CD8+ T cells in response to immunization with bead-bound and cell-associated antigens. Together, our data indicate the presence of dedicated apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDCs to facilitate XP.
传统的树突状细胞（cDCs）能产生针对细胞外病原体和肿瘤的保护性细胞毒性 T 淋巴细胞（CTL）反应。尽管XP具有重要的生物学意义，但其驱动机制仍不清楚。在这里，我们发现一种叫做脂蛋白 L 7C （APOL7C）的 cDC 特异性孔形成蛋白在先天性免疫刺激下上调，并被招募到吞噬体中。APOL7C 与吞噬体的结合导致吞噬体破裂，被吞噬的抗原逃逸到细胞膜，在细胞膜上通过内源性 MHC I 类抗原处理途径进行处理。因此，缺乏 APOL7C 的小鼠在对珠状抗原和细胞相关抗原进行免疫时不能有效地激发 CD8 + T 细胞。总之，我们的数据表明，存在一种专用的脂蛋白，它能介导将吞噬的蛋白质输送到活化的 cDCs 的细胞质中，从而促进 XP 的产生。
{"title":"The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells","authors":"Gerone A. Gonzales, Song Huang, Liam Wilkinson, Jenny A. Nguyen, Saif Sikdar, Cécile Piot, Victor Naumenko, Jahanara Rajwani, Cassandra M. Wood, Irene Dinh, Melanie Moore, Eymi Cedeño, Neil McKenna, Maria J. Polyak, Sara Amidian, Vincent Ebacher, Nicole L. Rosin, Matheus B. Carneiro, Bas Surewaard, Nathan C. Peters, Christopher H. Mody, Jeff Biernaskie, Robin M. Yates, Douglas J. Mahoney, Johnathan Canton","doi":"10.1126/sciimmunol.adn2168","DOIUrl":"10.1126/sciimmunol.adn2168","url":null,"abstract":"<div >Conventional dendritic cells (cDCs) generate protective cytotoxic T lymphocyte (CTL) responses against extracellular pathogens and tumors. This is achieved through a process known as cross-presentation (XP), and, despite its biological importance, the mechanism(s) driving XP remains unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein L 7C (APOL7C) is up-regulated in response to innate immune stimuli and is recruited to phagosomes. Association of APOL7C with phagosomes led to phagosomal rupture and escape of engulfed antigens to the cytosol, where they could be processed via the endogenous MHC class I antigen processing pathway. Accordingly, mice deficient in APOL7C did not efficiently prime CD8<sup>+</sup> T cells in response to immunization with bead-bound and cell-associated antigens. Together, our data indicate the presence of dedicated apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDCs to facilitate XP.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adu0981
Aron Gyorgypal, Robert M. Anthony
TP53 mutation triggers IL-34 secretion by cancer stem cells, reprogramming macrophages to suppress T cells and promote tumor immune escape.
TP53突变引发癌症干细胞分泌IL-34，使巨噬细胞重新编程，从而抑制T细胞，促进肿瘤免疫逃逸。
{"title":"TAM-ing the beast with IL-34 blockade","authors":"Aron Gyorgypal, Robert M. Anthony","doi":"10.1126/sciimmunol.adu0981","DOIUrl":"10.1126/sciimmunol.adu0981","url":null,"abstract":"<div ><i>TP53</i> mutation triggers IL-34 secretion by cancer stem cells, reprogramming macrophages to suppress T cells and promote tumor immune escape.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1126/sciimmunol.adp0707
Marta T. Borowska, Liu D. Liu, Nathanael A. Caveney, Kevin M. Jude, Won-Ju Kim, Takeya Masubuchi, Enfu Hui, Robbie G. Majzner, K. Christopher Garcia
CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as “beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.
CD45 是一种细胞表面磷酸酶，可形成 T 细胞受体信号阈值，但没有已知的配体。包括 E3/49K 在内的一系列腺病毒蛋白通过与 CD45 的细胞外结构域结合，抑制 T 细胞信号传导，从而利用 CD45 逃避免疫。我们测定了这一复合物的低温电子显微镜结构，发现 E3/49K 蛋白由三个免疫球蛋白结构域组成，它们像 "串珠 "一样组装在一起，通过交联 CD45 D3 结构域迫使 CD45 变成一个紧密相连的二聚体，从而导致其细胞内磷酸酶活性受到立体抑制。受 E3/49K 机制的启发，我们设计出了 CD45 替代配体，它们可以通过将 CD45 二聚为不同的方向和接近度来微调 T 细胞的活化。腺病毒 E3/49K 蛋白告诉我们，尽管缺乏已知的配体，但 CD45 的活性可以通过细胞外二聚配体来调节，从而扰乱其磷酸酶活性并改变 T 细胞的反应。
{"title":"Orientation-dependent CD45 inhibition with viral and engineered ligands","authors":"Marta T. Borowska, Liu D. Liu, Nathanael A. Caveney, Kevin M. Jude, Won-Ju Kim, Takeya Masubuchi, Enfu Hui, Robbie G. Majzner, K. Christopher Garcia","doi":"10.1126/sciimmunol.adp0707","DOIUrl":"10.1126/sciimmunol.adp0707","url":null,"abstract":"<div >CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as “beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1126/sciimmunol.ado0090
Francesca Cossarini, Joan Shang, Azra Krek, Zainab Al-Taie, Ruixue Hou, Pablo Canales-Herrerias, Minami Tokuyama, Michael Tankelevich, Adam Tillowitz, Divya Jha, Alexandra E. Livanos, Louise Leyre, Mathieu Uzzan, Gustavo Martinez-Delgado, Matthew D. Taylor, Keshav Sharma, Arno R. Bourgonje, Michael Cruz, Giorgio Ioannou, Travis Dawson, Darwin D''Souza, Seunghee Kim-Schulze, Ahmed Akm, Judith A. Aberg, Benjamin K. Chen, Douglas S. Kwon, Sacha Gnjatic, Alexandros D. Polydorides, Andrea Cerutti, Carmen Argmann, Ivan Vujkovic-Cvijin, Mayte Suarez-Fariñas, Francesca Petralia, Jeremiah J. Faith, Saurabh Mehandru
Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A–positive (IgA+) PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)–treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.
胃肠道（GI）B细胞和浆细胞（PC）对粘膜平衡和宿主对HIV-1感染的反应至关重要。在这里，我们对在HIV-1病毒感染和抑制感染期间从结肠和回肠取样的人类B细胞和浆细胞进行了高分辨率绘图，发现在HIV-1病毒血症期间，生殖中心（GC）B细胞和滤泡树突状细胞（FDCs）减少了。免疫球蛋白 A 阳性（IgA + ）PC 是肠道 GC 的主要细胞输出，在 HIV-1 病毒感染期间显著减少。在接受抗逆转录病毒疗法（ART）治疗的个体中，PC相关的转录扰动（包括I型干扰素信号转导）持续存在，这表明在抗逆转录病毒疗法期间肠道免疫环境持续受到破坏。肠道体液免疫扰动与肠道微生物组组成的变化和全身炎症有关。这些发现凸显了HIV-1病毒血症导致的消化道粘膜主要免疫缺陷。
{"title":"Gastrointestinal germinal center B cell depletion and reduction in IgA+ plasma cells in HIV-1 infection","authors":"Francesca Cossarini, Joan Shang, Azra Krek, Zainab Al-Taie, Ruixue Hou, Pablo Canales-Herrerias, Minami Tokuyama, Michael Tankelevich, Adam Tillowitz, Divya Jha, Alexandra E. Livanos, Louise Leyre, Mathieu Uzzan, Gustavo Martinez-Delgado, Matthew D. Taylor, Keshav Sharma, Arno R. Bourgonje, Michael Cruz, Giorgio Ioannou, Travis Dawson, Darwin D''Souza, Seunghee Kim-Schulze, Ahmed Akm, Judith A. Aberg, Benjamin K. Chen, Douglas S. Kwon, Sacha Gnjatic, Alexandros D. Polydorides, Andrea Cerutti, Carmen Argmann, Ivan Vujkovic-Cvijin, Mayte Suarez-Fariñas, Francesca Petralia, Jeremiah J. Faith, Saurabh Mehandru","doi":"10.1126/sciimmunol.ado0090","DOIUrl":"10.1126/sciimmunol.ado0090","url":null,"abstract":"<div >Gastrointestinal (GI) B cells and plasma cells (PCs) are critical to mucosal homeostasis and the host response to HIV-1 infection. Here, high-resolution mapping of human B cells and PCs sampled from the colon and ileum during both viremic and suppressed HIV-1 infection identified a reduction in germinal center (GC) B cells and follicular dendritic cells (FDCs) during HIV-1 viremia. Immunoglobulin A–positive (IgA<sup>+</sup>) PCs are the major cellular output of intestinal GCs and were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling, persisted in antiretroviral therapy (ART)–treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations were associated with changes in the intestinal microbiome composition and systemic inflammation. These findings highlight a key immune defect in the GI mucosa due to HIV-1 viremia.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ado0090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adt4547
{"title":"Erratum for the Research Article “Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium” by K. Liang et al.","authors":"","doi":"10.1126/sciimmunol.adt4547","DOIUrl":"10.1126/sciimmunol.adt4547","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adt4549
{"title":"Erratum for the Research Article “Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident” by E. D. Lucas et al.","authors":"","doi":"10.1126/sciimmunol.adt4549","DOIUrl":"10.1126/sciimmunol.adt4549","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adn9879
Fangda Li, Zaofeng Yang, Thomas M. Savage, Rosa L. Vincent, Kenia de los Santos-Alexis, Alexander Ahn, Mathieu Rouanne, Dylan L. Mariuzza, Tal Danino, Nicholas Arpaia
Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3−CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.
{"title":"Programmable bacteria synergize with PD-1 blockade to overcome cancer cell–intrinsic immune resistance mechanisms","authors":"Fangda Li, Zaofeng Yang, Thomas M. Savage, Rosa L. Vincent, Kenia de los Santos-Alexis, Alexander Ahn, Mathieu Rouanne, Dylan L. Mariuzza, Tal Danino, Nicholas Arpaia","doi":"10.1126/sciimmunol.adn9879","DOIUrl":"10.1126/sciimmunol.adn9879","url":null,"abstract":"<div >Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3<sup>−</sup>CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn9879","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adg6453
Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L. Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G. Engleman
Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.
{"title":"The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity","authors":"Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L. Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G. Engleman","doi":"10.1126/sciimmunol.adg6453","DOIUrl":"10.1126/sciimmunol.adg6453","url":null,"abstract":"<div >Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell–derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adg6453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-18DOI: 10.1126/sciimmunol.adl2986
Haerin Jung, Do-Hyun Kim, Roberto Efraín Díaz, J. Michael White, Summer Rucknagel, Lauryn Mosby, Yilin Wang, Sanjana Reddy, Emma S. Winkler, Ahmed O. Hassan, Baoling Ying, Michael S. Diamond, Richard M. Locksley, James S. Fraser, Steven J. Van Dyken
Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.
{"title":"An ILC2-chitinase circuit restores lung homeostasis after epithelial injury","authors":"Haerin Jung, Do-Hyun Kim, Roberto Efraín Díaz, J. Michael White, Summer Rucknagel, Lauryn Mosby, Yilin Wang, Sanjana Reddy, Emma S. Winkler, Ahmed O. Hassan, Baoling Ying, Michael S. Diamond, Richard M. Locksley, James S. Fraser, Steven J. Van Dyken","doi":"10.1126/sciimmunol.adl2986","DOIUrl":"10.1126/sciimmunol.adl2986","url":null,"abstract":"<div >Environmental exposures increase the risk for severe lung disease, but specific drivers of persistent epithelial injury and immune dysfunction remain unclear. Here, we identify a feedback circuit triggered by chitin, a common component of airborne particles, that affects lung health after epithelial injury. In mice, epithelial damage disrupts lung chitinase activity, leading to environmental chitin accumulation, impaired epithelial renewal, and group 2 innate lymphoid cell (ILC2) activation. ILC2s, in turn, restore homeostasis by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells and promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear chitin and exhibit increased mortality and impaired epithelial regeneration after injury. These effects are ameliorated by chitinase replacement therapy, demonstrating that chitin degradation is crucial for recovery after various forms of lung perturbation. Thus, the ILC2-chitinase response circuit may serve as a target for alleviating persistent postinjury lung epithelial and immune dysfunction.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 100","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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