Pub Date : 2024-05-31DOI: 10.1126/sciimmunol.adq3385
{"title":"Erratum for the Research Article “TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf” by Y. Chang et al.","authors":"","doi":"10.1126/sciimmunol.adq3385","DOIUrl":"10.1126/sciimmunol.adq3385","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184465","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 : 2024-05-31DOI: 10.1126/sciimmunol.adj2654
Qiutong Huang, Wang H. J. Cao, Sophie Curio, Huiyang Yu, Renae Denman, Evelyn Chen, Jaring Schreuder, James Dight, M. Zeeshan Chaudhry, Nicolas Jacquelot, Verena C. Wimmer, Cyril Seillet, Tarik Möröy, Gabrielle T. Belz
Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B+ lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R+ ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge.
{"title":"GFI1B specifies developmental potential of innate lymphoid cell progenitors in the lungs","authors":"Qiutong Huang, Wang H. J. Cao, Sophie Curio, Huiyang Yu, Renae Denman, Evelyn Chen, Jaring Schreuder, James Dight, M. Zeeshan Chaudhry, Nicolas Jacquelot, Verena C. Wimmer, Cyril Seillet, Tarik Möröy, Gabrielle T. Belz","doi":"10.1126/sciimmunol.adj2654","DOIUrl":"10.1126/sciimmunol.adj2654","url":null,"abstract":"<div >Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B<sup>+</sup> lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R<sup>+</sup> ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184449","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 : 2024-05-31DOI: 10.1126/sciimmunol.adl2171
Sai Xiao, Shoubao Ma, Baofa Sun, Wenchen Pu, Songqi Duan, Jingjing Han, Yaqun Hong, Jianying Zhang, Yong Peng, Chuan He, Ping Yi, Michael A. Caligiuri, Jianhua Yu
Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain–containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell–mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti–PD-L1 or anti–PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
肿瘤通过各种机制逃避免疫系统的攻击。在这里，我们发现了由含YTH结构域的家族蛋白2（YTHDF2）介导的肿瘤免疫逃避的一个组成部分，YTHDF2是一种阅读蛋白，通常会破坏m6A修饰的mRNA的稳定性。在免疫功能正常的肿瘤模型中，肿瘤 YTHDF2 的缺失可抑制肿瘤生长并延长存活时间。从机理上讲，肿瘤 YTHDF2 缺乏会通过 CX3CL1 促进巨噬细胞的招募，并通过损害肿瘤糖酵解代谢增强 CD8+ T 细胞的线粒体呼吸。在有 IFN-γ 的情况下，肿瘤 YTHDF2 缺乏会促进炎性巨噬细胞极化和抗原递呈。此外，IFN-γ 还能诱导肿瘤 YTHDF2 自噬降解，从而使肿瘤细胞对 CD8+ T 细胞介导的细胞毒性敏感。最后，我们发现了一种能优先诱导YTHDF2降解的小分子化合物，这种化合物单独使用时具有强效抗肿瘤作用，但与抗PD-L1或抗PD-1抗体联合使用时效果更好。总之，YTHDF2似乎是一种协调免疫逃避的肿瘤内在调控因子，是增强癌症免疫疗法的一个有希望的靶点。
{"title":"The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion","authors":"Sai Xiao, Shoubao Ma, Baofa Sun, Wenchen Pu, Songqi Duan, Jingjing Han, Yaqun Hong, Jianying Zhang, Yong Peng, Chuan He, Ping Yi, Michael A. Caligiuri, Jianhua Yu","doi":"10.1126/sciimmunol.adl2171","DOIUrl":"10.1126/sciimmunol.adl2171","url":null,"abstract":"<div >Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain–containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m<sup>6</sup>A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8<sup>+</sup> T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8<sup>+</sup> T cell–mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti–PD-L1 or anti–PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adl2171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184478","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 : 2024-05-24DOI: 10.1126/sciimmunol.ade2094
Munetomo Takahashi, Tsz Y. So, Vitalina Chamberlain-Evans, Robert Hughes, Juan Carlos Yam-Puc, Katarzyna Kania, Michelle Ruhle, Tiffeney Mann, Martijn J. Schuijs, Paul Coupland, Dean Naisbitt, Timotheus Y. F. Halim, Paul A. Lyons, Pietro Lio, Rahul Roychoudhuri, Klaus Okkenhaug, David J. Adams, Ken G. C. Smith, Duncan I. Jodrell, Michael A. Chapman, James E. D. Thaventhiran
Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8+ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (Treg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8+ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.
由于难以追踪淋巴细胞在抗原信号转导后的行为，免疫疗法的进展受到了阻碍。在这里，我们通过开发抗原受体信号转导报告（AGRSR）小鼠来评估活跃在肿瘤内的T细胞的行为，对在特定时间和位置对抗原做出反应的淋巴细胞进行命运图谱绘制。与T细胞可随时排出肿瘤的报道相反，我们发现瘤内抗原信号将CD8+ T细胞困在肿瘤内。随着时间的推移，这些克隆细胞群不断扩大并日益衰竭。相比之下，抗原信号调节性 T 细胞（Treg）克隆群很容易再循环到肿瘤外。因此，瘤内抗原信号起到了看门人的作用，将 CD8+ T 细胞反应分隔开来，即使在同一克隆类型中也是如此，从而使衰竭的 T 细胞局限于特定的肿瘤组织部位。
{"title":"Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site","authors":"Munetomo Takahashi, Tsz Y. So, Vitalina Chamberlain-Evans, Robert Hughes, Juan Carlos Yam-Puc, Katarzyna Kania, Michelle Ruhle, Tiffeney Mann, Martijn J. Schuijs, Paul Coupland, Dean Naisbitt, Timotheus Y. F. Halim, Paul A. Lyons, Pietro Lio, Rahul Roychoudhuri, Klaus Okkenhaug, David J. Adams, Ken G. C. Smith, Duncan I. Jodrell, Michael A. Chapman, James E. D. Thaventhiran","doi":"10.1126/sciimmunol.ade2094","DOIUrl":"10.1126/sciimmunol.ade2094","url":null,"abstract":"<div >Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8<sup>+</sup> T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (T<sub>reg</sub>) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8<sup>+</sup> T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093251","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}
Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor–β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of “stress memory.”
{"title":"Heart failure promotes multimorbidity through innate immune memory","authors":"Yukiteru Nakayama, Katsuhito Fujiu, Tsukasa Oshima, Jun Matsuda, Junichi Sugita, Takumi James Matsubara, Yuxiang Liu, Kohsaku Goto, Kunihiro Kani, Ryoko Uchida, Norifumi Takeda, Hiroyuki Morita, Yingda Xiao, Michiko Hayashi, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Soh Ishiguro, Yusuke Kijima, Nozomu Yachie, Satoshi Yamazaki, Ryo Yamamoto, Fujimi Kudo, Mio Nakanishi, Atsushi Iwama, Ryoji Fujiki, Atsushi Kaneda, Osamu Ohara, Ryozo Nagai, Ichiro Manabe, Issei Komuro","doi":"10.1126/sciimmunol.ade3814","DOIUrl":"10.1126/sciimmunol.ade3814","url":null,"abstract":"<div >Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor–β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of “stress memory.”</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ade3814","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093294","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 : 2024-05-24DOI: 10.1126/sciimmunol.ade5705
Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D.P. Willet, Kieran D. James, Edward J. Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L. Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J. Swan, Valeria Pintar, Kamal Sayes, Elias R. Ruiz-Morales, Simon Eastham, David Dixon, Martin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R. Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R. Gennery, Matthias Trost, David J. Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton
Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 (NUDCD3). Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T -B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.
先天性 T 细胞发育异常是一种儿科急症，及时的治疗方法取决于分子诊断。在 4 个近亲血统的 11 名患者中，我们检测到了含 NudC 结构域的 3（NUDCD3）基因的单个有害错义变异的同源性。两名婴儿患有严重的联合免疫缺陷症，T 细胞和 B 细胞完全缺失（T -B- SCID），而九名婴儿则表现出典型的奥门综合征（OS）特征。残余T淋巴细胞的抗原受体基因使用受限，表明V（D）J重组受损。患者细胞的NUDCD3蛋白表达量减少，体外支持RAG介导的重组的能力减弱，这与核小体中RAG1的病理性固着有关。虽然在携带同源变异体的小鼠模型中，V（D）J 重组受损会导致较轻微的免疫异常，但 NUDCD3 绝对是人类 T 细胞和 B 细胞健康发育所必需的。
{"title":"NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome","authors":"Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D.P. Willet, Kieran D. James, Edward J. Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L. Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J. Swan, Valeria Pintar, Kamal Sayes, Elias R. Ruiz-Morales, Simon Eastham, David Dixon, Martin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R. Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R. Gennery, Matthias Trost, David J. Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton","doi":"10.1126/sciimmunol.ade5705","DOIUrl":"10.1126/sciimmunol.ade5705","url":null,"abstract":"<div >Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 (<i>NUDCD3</i>)<i>.</i> Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T<sup> -</sup>B<sup>-</sup> SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ade5705","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093322","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 : 2024-05-17DOI: 10.1126/sciimmunol.adi5374
Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
{"title":"TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti–PD-1 tumor immunotherapy","authors":"Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna","doi":"10.1126/sciimmunol.adi5374","DOIUrl":"10.1126/sciimmunol.adi5374","url":null,"abstract":"<div >The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of <i>Ruminococcus gnavus</i> in the gut microbiota. Gavage of wild-type mice with <i>R. gnavus</i> enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4<sup>+</sup> T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with <i>R. gnavus</i> emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953857","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 : 2024-05-17DOI: 10.1126/sciimmunol.adi7418
Hieu Minh Ta, Dia Roy, Keman Zhang, Tyler Alban, Ivan Juric, Juan Dong, Prerana B. Parthasarathy, Sachin Patnaik, Elizabeth Delaney, Cassandra Gilmour, Amin Zakeri, Nidhi Shukla, Amit Rupani, Yee Peng Phoon, Caini Liu, Stefanie Avril, Brian Gastman, Timothy Chan, Li Lily Wang
Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1+ CD62Lhi PD-1low) and a reciprocal increase in progenitor and memory-like CTLs (TCF1+ PD-1+). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.
免疫检查点阻断是激活抗肿瘤免疫力和提高癌症患者生存率的一种很有前景的方法。V域免疫球蛋白T细胞活化抑制因子（VISTA）是一种免疫检查点靶点；然而，其下游信号机制却难以捉摸。在这里，我们发现富亮氨酸重复序列和免疫球蛋白样结构域1（LRIG1）是VISTA的结合伙伴，它作为抑制受体与VISTA结合并抑制T细胞受体信号通路。由于肿瘤特异性细胞毒性 T 淋巴细胞（CTL）扩增，效应功能增强，存活率提高，因此缺失 T 细胞特异性 LRIG1 的小鼠产生了卓越的抗肿瘤反应。肿瘤的持续控制与静止 CTL（TCF1 + CD62L hi PD-1 low）的减少以及祖细胞和记忆样 CTL（TCF1 + PD-1 +）的对等增加有关。在黑色素瘤患者中，肿瘤浸润 CD8 + CTL 上 LRIG1 表达的升高与免疫疗法的抗药性相关。这些结果阐明了 LRIG1 作为抑制性免疫检查点受体的作用，并提出了针对 VISTA/LRIG1 轴进行癌症免疫疗法的理论依据。
{"title":"LRIG1 engages ligand VISTA and impairs tumor-specific CD8+ T cell responses","authors":"Hieu Minh Ta, Dia Roy, Keman Zhang, Tyler Alban, Ivan Juric, Juan Dong, Prerana B. Parthasarathy, Sachin Patnaik, Elizabeth Delaney, Cassandra Gilmour, Amin Zakeri, Nidhi Shukla, Amit Rupani, Yee Peng Phoon, Caini Liu, Stefanie Avril, Brian Gastman, Timothy Chan, Li Lily Wang","doi":"10.1126/sciimmunol.adi7418","DOIUrl":"10.1126/sciimmunol.adi7418","url":null,"abstract":"<div >Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1<sup>+</sup> CD62L<sup>hi</sup> PD-1<sup>low</sup>) and a reciprocal increase in progenitor and memory-like CTLs (TCF1<sup>+</sup> PD-1<sup>+</sup>). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8<sup>+</sup> CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953853","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 : 2024-05-16DOI: 10.1126/sciimmunol.adn0622
Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
胚系靶向（GT）蛋白免疫原可诱导针对艾滋病病毒包膜（Env）CD4结合位点的VRC01级广谱中和抗体（bnAbs），已在临床试验中显示出良好的前景。在这里，我们在小鼠模型中对编码 eOD-GT8 60mer 的脂质纳米颗粒封装核苷 mRNA（mRNA-LNP）作为可溶性自组装纳米颗粒进行了临床前验证。在具有三个人源化 B 细胞系的模型中，这些细胞系都带有不同的 VRC01 前体 B 细胞受体（BCR），它们对 eOD-GT8 具有相似的亲和力。增殖推动了前体 B 细胞参与生殖中心；体细胞高突变的积累，包括在关键的 VRC01 类位置；以及三个前体系中两个系对增殖抗原和类原生抗原的亲和性成熟。我们在临床前验证了由 mRNA-LNP 编码的可溶性自组装纳米粒子的启动-启动方案，证明了多系细胞可沿着 bnAb 途径启动、启动和多样化。
{"title":"mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models","authors":"Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista","doi":"10.1126/sciimmunol.adn0622","DOIUrl":"10.1126/sciimmunol.adn0622","url":null,"abstract":"<div >Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn0622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953313","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 : 2024-05-10DOI: 10.1126/sciimmunol.adn0126
Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, Rodrigo Colombo, Julian Spagnuolo, Giuliano Berloffa, Daniel Joss, Ove Øyås, Chiara Lecchi, Giulia De Simone, Aisha Beshirova, Vladimir Nosi, José Pedro Loureiro, Aurelia Morabito, Corinne De Gregorio, Michael Pfeffer, Verena Schaefer, Gennaro Prota, Alfred Zippelius, Jörg Stelling, Daniel Häussinger, Laura Brunelli, Peter Villalta, Marco Lepore, Enrico Davoli, Silvia Balbo, Lucia Mori, Gennaro De Libero
MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I–related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.
MR1T 细胞是最近发现的一类 T 细胞，它们能在没有微生物感染的情况下识别由主要组织相容性复合体 I 相关分子 MR1 呈递的抗原。刺激 MR1T 细胞的自身抗原的性质仍不清楚，这妨碍了我们对其生理作用和治疗潜力的了解。通过结合遗传学、药理学和生物化学方法，我们发现靶细胞中的羰基应激和核碱基代谢变化会促进 MR1T 细胞的活化。在肿瘤细胞产生的 MR1 分子中检测到了由核碱基的羰基加合物形成的刺激性化合物，诱导羰基积累的药物增强了这些化合物的丰度和抗原性。我们的数据揭示了羰基核碱基加合物是 MR1T 细胞抗原。通过识别羰基压力下的细胞，MR1T 细胞可以监测细胞代谢变化，从而产生生理和治疗意义。
{"title":"Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells","authors":"Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, Rodrigo Colombo, Julian Spagnuolo, Giuliano Berloffa, Daniel Joss, Ove Øyås, Chiara Lecchi, Giulia De Simone, Aisha Beshirova, Vladimir Nosi, José Pedro Loureiro, Aurelia Morabito, Corinne De Gregorio, Michael Pfeffer, Verena Schaefer, Gennaro Prota, Alfred Zippelius, Jörg Stelling, Daniel Häussinger, Laura Brunelli, Peter Villalta, Marco Lepore, Enrico Davoli, Silvia Balbo, Lucia Mori, Gennaro De Libero","doi":"10.1126/sciimmunol.adn0126","DOIUrl":"10.1126/sciimmunol.adn0126","url":null,"abstract":"<div >MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I–related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905011","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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