Research Article
Abstract
The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosal-associated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1*01 and/or MR1*02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3–5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.
Authors
Garry Dolton, Hannah Thomas, Li Rong Tan, Cristina Rius Rafael, Stephanie Doetsch, Giulia-Andreea Ionescu, Lucia F. Cardo, Michael D. Crowther, Enas Behiry, Théo Morin, Marine E. Caillaud, Devinder Srai, Lucia Parolini, Md Samiul Hasan, Anna Fuller, Katie Topley, Aaron Wall, Jade R. Hopkins, Nader Omidvar, Caroline Alvares, Joanna Zabkiewicz, John Frater, Barbara Szomolay, Andrew K. Sewell
Abstract
Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer’s disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.
Authors
Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong
Abstract
The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus–5-fluorouracil (calcipotriol-plus–5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus–5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus–5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.
Authors
Tomonori Oka, Sabrina S. Smith, Heehwa G. Son, Truelian Lee, Valeria S. Oliver-Garcia, Mahsa Mortaja, Kathryn E. Trerice, Lily S. Isakoff, Danielle N. Conrad, Marjan Azin, Neel S. Raval, Mary Tabacchi, Luni Emdad, Swadesh K. Das, Paul B. Fisher, Lynn A. Cornelius, Shadmehr Demehri
Abstract
Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.
Authors
Yanni Zeng, Chun-Ling Luo, Guo-Wang Lin, Fugui Li, Xiaomeng Bai, Josephine Mun-Yee Ko, Lei Xiong, Yang Liu, Shuai He, Jia-Xin Jiang, Wen-Xin Yan, Enya Hui Wen Ong, Zheng Li, Ya-Qing Zhou, Yun-He Zhou, An-Yi Xu, Shu-Qiang Liu, Yun-Miao Guo, Jie-Rong Chen, Xi-Xi Cheng, Yu-Lu Cao, Xia Yu, Biaohua Wu, Pan-Pan Wei, Zhao-Hui Ruan, Qiu-Yan Chen, Lin-Quan Tang, James D. McKay, Wei-Hua Jia, Hai-Qiang Mai, Soon Thye Lim, Jian-Jun Liu, Dong-Xin Lin, Chiea Chuen Khor, Melvin Lee Kiang Chua, Mingfang Ji, Maria Li Lung, Yi-Xin Zeng, Jin-Xin Bei
Abstract
Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset’s contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps. We found that short-term TGF-β signaling alters MC cell surface receptor expression and partially recapitulated the in vivo MCT transcriptome, while TGF-β signaling during MC differentiation upregulated a larger number of MCT-associated transcripts. TGF-β inhibited the hallmark MCTC proteases chymase and cathepsin G at both the transcript and protein level, allowing selective in vitro differentiation of MCTs for functional study. We identified discrete differences in effector phenotype between in vitro–derived MCTs and MCTCs, with MCTs exhibiting enhanced proinflammatory lipid mediator generation and a distinct cytokine, chemokine, and growth factor production profile in response to both innate and adaptive stimuli, recapitulating functional features of their tissue-associated counterpart MC subsets. Thus, our findings support a role for TGF-β in promoting human MCT differentiation and identified a discrete contribution of this cell type to T2 inflammation.
Authors
Tahereh Derakhshan, Eleanor Hollers, Alex Perniss, Tessa Ryan, Alanna McGill, Jonathan Hacker, Regan W. Bergmark, Neil Bhattacharyya, Stella E. Lee, Alice Z. Maxfield, Rachel E. Roditi, Lora Bankova, Kathleen M. Buchheit, Tanya M. Laidlaw, Joshua A. Boyce, Daniel F. Dwyer
Abstract
The risk of severe outcomes of influenza increases during pregnancy. Whether vaccine-induced T cell memory–primed prepregnancy retains the ability to mediate protection during pregnancy, when systemic levels of several hormones with putative immunomodulatory functions are increased, is unknown. Here, using murine adoptive transfer systems and a translationally relevant model of cold-adapted live-attenuated influenza A virus vaccination, we show that preexisting virus-specific memory T cell responses are largely unaltered and highly protective against heterotypic viral challenges during pregnancy. Expression of the transcription factor T-bet, which is upregulated in antiviral T cells responding in pregnant mice, is critical in preventing hormone-associated gain of detrimental T helper type 2 (TH2) attributes reported in other settings. Beyond antiviral effects, preexisting vaccine-primed T cell immunity prevents metabolic dysfunction in gravid dams and adverse neonatal outcomes often associated with maternal influenza infection. These results demonstrate robust protection of the maternal-fetal unit from severe consequences of respiratory virus infection by preexisting T cell immunity.
Authors
Valeria Flores Malavet, Kunal Dhume, Ali Satchmei, Andrea C. Arvelo, Aaron J. Beaird, Siva N. Annamalai, Lauren A. Kimball, K. Kai McKinstry, Tara M. Strutt
Abstract
ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture of Atrx conditional knockout bone marrow stromal cells (BMSCs) with WT splenocytes showed impaired osteoclast differentiation. Additionally, Atrx deletion was associated with decreased receptor activator of nuclear factor κ-B ligand (Rankl)/ osteoprotegerin (Opg) expression ratio in BMSCs. Notably, Atrx-deficient osteolineage cells expressed high levels of the neuropeptide cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt). Mechanistically, ATRX suppresses Cartpt transcription by binding to the promoter, which is otherwise poised for Cartpt expression by RUNX2 binding to the distal enhancer. Finally, Cartpt silencing in Atrx conditional knockout BMSCs rescued the molecular phenotype by increasing the Rankl/Opg expression ratio. Together, our data show a potent repressor function of ATRX in restricting Cartpt expression during skeletal development.
Authors
Yi-Ting Chen, Ming-Ming Jiang, Carolina Leynes, Mary Adeyeye, Camilla F. Majano, Barakat Ibrahim, Urszula Polak, George Hung, Zixue Jin, Denise G. Lanza, Lan Liao, Brian Dawson, Yuqing Chen-Evenson, Oscar E. Ruiz, Richard J. Gibbons, Jason D. Heaney, Yangjin Bae, Brendan Lee
Abstract
mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines. We first immunized mice with mRNA vaccines, followed by treatment with 4-1BB costimulatory antibodies to reinforce the 4-1BB pathway at different time points after vaccination. Consistent with prior studies, reinforcing 4-1BB costimulation on the day of vaccination did not result in a substantial improvement in vaccine responses. However, reinforcing 4-1BB costimulation on day 4 after vaccination, when 4-1BB expression levels were highest, resulted in a profound improvement in CD8+ T cell responses associated with enhanced protection against pathogen challenges. A similar clinical benefit was observed in a therapeutic cancer vaccine model. We also report time-dependent effects with OX40, another costimulatory molecule of the TNF receptor superfamily. These findings demonstrate that delayed reinforcement of costimulation may exert an immunologic benefit, providing insights for the development of more effective mRNA vaccines for infectious diseases and cancer.
Authors
Sarah Sanchez, Tanushree Dangi, Bakare Awakoaiye, Min Han Lew, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster
Abstract
Heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) represent starkly diverging clinical phenotypes, yet may be caused by mutations to the same sarcomeric protein. The precise mechanisms by which point mutations within the same gene bring about phenotypic diversity remain unclear. Our objective was to develop a mechanistic explanation of diverging phenotypes in two TPM1 mutations, E62Q (HCM) and E54K (DCM). Drawing on data from the literature and experiments with stem cell–derived cardiomyocytes expressing the TPM1 mutations of interest, we constructed computational simulations that provide plausible explanations of the distinct muscle contractility caused by each variant. In E62Q, increased calcium sensitivity and hypercontractility was explained most accurately by a reduction in effective molecular stiffness of tropomyosin and alterations in its interactions with the actin thin filament that favor the “closed” regulatory state. By contrast, the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin. These mutation-linked molecular events produced diverging alterations in gene expression that can be observed in human engineered heart tissues. Modulators of myosin activity confirmed our proposed mechanisms by rescuing normal contractile behavior in accordance with predictions.
Authors
Saiti S. Halder, Michael J. Rynkiewicz, Lynne Kim, Meaghan E. Barry, Ahmed G.A. Zied, Lorenzo R. Sewanan, Jonathan A. Kirk, Jeffrey R. Moore, William J. Lehman, Stuart G. Campbell
Abstract
Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor–based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid–binding immunoglobulin-like lectins) are expressed on immune cells and regulate their function. Siglec-7 and Siglec-9 contribute to immune evasion in cancer by interacting with sialic acid–containing glycoprotein ligands on cancer cells. However, the role of Siglec-7/9 receptors and their ligands in prostate cancer remains poorly understood. Here, we find that Siglec-7 and Siglec-9 are associated with poor prognosis in patients with prostate cancer and are highly expressed in myeloid cells, including macrophages, in prostate tumor tissues. Siglec-7 and -9 ligands were expressed in prostate cancer cells and human prostate tumor tissues. Blocking the interactions between Siglec-7/9 and sialic acids inhibited prostate cancer xenograft growth and increased immune cell infiltration in humanized mice in vivo. Using a CRISPRi screen and mass spectrometry, we identified CD59 as a candidate Siglec-9 ligand in prostate cancer. The identification of Siglec-7 and -9 as potential therapeutic targets, including the CD59/Siglec-9 axis, opens up opportunities for immune-based interventions in prostate cancer.
Authors
Ru M. Wen, Jessica C. Stark, G. Edward W. Marti, Zenghua Fan, Aram Lyu, Fernando Jose Garcia Marques, Xiangyue Zhang, Nicholas M. Riley, Sarah M. Totten, Abel Bermudez, Rosalie Nolley, Hongjuan Zhao, Lawrence Fong, Edgar G. Engleman, Sharon J. Pitteri, Carolyn R. Bertozzi, James D. Brooks
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ISSN: 0021-9738 (print), 1558-8238 (online)