Stimulation of TAM (TYRO3, AXL and MERTK) Receptor Tyrosine Kinases promotes tumor progression through numerous cellular mechanisms. TAM cognate ligands GAS6 and PROS1 (for TYRO3 and MERTK) are secreted by host immune cells, an interaction which may support tumor progression. Here we reveal an unexpected anti-metastatic role for myeloid-derived PROS1, directly suppressing the metastatic potential of lung and breast tumor models. Pros1 deletion in myeloid cells led to increased lung metastasis, independent of primary tumor infiltration. PROS1-cKO BMDMs led to elevated TNFα, IL-6, Nos2 and IL-10 via modulation of the Socs3-NFκB pathway. Conditioned medium from cKO BMDMs enhanced EMT, ERK, AKT and STAT3 activation within tumor cells, and promoted IL-10 dependent invasion and survival. Macrophages isolated from metastatic lungs modulated T cell proliferation and function, as well as expression of costimulatory molecules on dendritic cells in a PROS1-dependent manner. Inhibition of MERTK kinase activity blocked PROS1-mediated suppression of TNFα and IL-6, but not of IL-10. Overall, using lung and breast cancer models, we identify the PROS1-MERTK axis within BMDMs as a potent regulator of adaptive immune responses with a potential to suppress metastatic seeding, and reveal IL-10 regulation by PROS1 to deviate from that of TNFα and IL-6.
Avi Maimon, Victor Levi-Yahid, Kerem Ben-Meir, Amit Halpern, Ziv Talmi, Shivam Priya, Gabriel Mizraji, Shani Mistriel-Zerbib, Michael Berger, Michal Baniyash, Sonja Loges, Tal Burstyn-Cohen
Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.
Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson
Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt, Paschold, and Rivas et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C.
Theodore Kouo, Worarat Chaisawangwong
Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.
Young Joo Sun, Gabriel Velez, Dylan E. Parsons, Kun Li, Miguel E. Ortiz, Shaunik Sharma, Paul B. McCray Jr., Alexander G. Bassuk, Vinit B. Mahajan
Background. Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to cross-recognition by T-cells specific for common cold coronaviruses (CCCs). True T-cell cross-reactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2. Methods. We used the ViraFEST platform to identify T cell responses cross-reactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC cross-reactivity and assessments of functional avidity were performed using a TCR cloning and transfection system. Results. Memory CD4+ T-cell clonotypes that cross-recognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Cross-reactive T-cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to mono-specific CD4+ T-cells, which was consistent with lower functional avidity of their TCRs for SARS CoV-2 relative to CCC. Conclusions. For the first time, our data confirm the existence of unique memory CD4+ T cell clonotypes cross-recognizing SARS-CoV-2 and CCCs. The lower avidity of cross-reactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that pre-existing CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these cross-reactive T-cell responses impact clinical outcomes in COVID-19 patients.
Arbor G. Dykema, Boyang Zhang, Bezawit A. Woldemeskel, Caroline C. Garliss, Laurene S. Cheung, Dilshad Choudhury, Jiajia Zhang, Luis Aparicio, Sadhana Bom, Rufiaat Rashid, Justina X. Caushi, Emily Han-Chung Hsiue, Katherine Cascino, Elizabeth A. Thompson, Abena K. Kwaa, Dipika Singh, Sampriti Thapa, Alvaro A. Ordonez, Andrew Pekosz, Franco R. D'Alessio, Jonathan D. Powell, Srinivasan Yegnasubramanian, Shibin Zhou, Drew M. Pardoll, Hongkai Ji, Andrea L. Cox, Joel N. Blankson, Kellie N. Smith
A complete carcinogen, Ultraviolet B radiation (290-320 nm; UVB), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator Platelet-activating factor. A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF Receptor (PAFR) activation in keratinocytes induce large amounts of microvesicle particle (extracellular vesicles 100-1000nm; MVP) release. MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVP) are dependent upon the keratinocyte PAFR. The present studies used both pharmacologic and genetic approaches in cells and mice to determine that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVP leaving the keratinocyte can be found systemically in mice and in human subjects following UVB. Moreover, UVB-MVP contain bioactive contents including PAFR agonists which allow them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.
Langni Liu, Azeezat A. Awoyemi, Katherine E. Fahy, Pariksha Thapa, Christina Borchers, Benita Y. Wu, Cameron L. McGlone, Benjamin Schmeusser, Zafer Sattouf, Craig A. Rohan, Amy R. Williams, Elizabeth E. Cates, Christina Knisely, Lisa E. Kelly, Ji C. Bihl, David R. Cool, Ravi P. Sahu, Jinju Wang, Yanfang Chen, Christine M. Rapp, Michael G. Kemp, R. Michael Johnson, Jeffrey B. Travers
One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I) that significantly promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced major histocompatibility class I (MHC-I)-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation, empowers T-cell cytotoxicity, and thus elevates the tumor response to immunotherapy.
Hanchen Xu, Kevin Van der Jeught, Zhuolong Zhou, Lu Zhang, Tao Yu, Yifan Sun, Yujing Li, Changlin Wan, Kaman So, Degang Liu, Michael Frieden, Yuanzhang Fang, Amber L. Mosley, Xiaoming He, Xinna Zhang, George E. Sandusky, Yunlong Liu, Samy O. Meroueh, Chi Zhang, Aruna B. Wijeratne, Cheng Huang, Guang Ji, Xiongbin Lu
BACKGROUND. Recently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiologic study of terazosin users showed a lower incidence of Parkinson disease when compared to users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group. METHODS. To address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the U.S.A. with > 5 years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690) or controls matched on age, gender and Charlson Comorbidity Index score (n = 45,380). RESULTS. Incidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%; p<0.0001) and matched controls (1.01%; p < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (p = 0.29). CONCLUSION. These results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression. FUNDING. This work was supported by Cerevel Therapeutics.
Rahul Sasane, Amy Bartels, Michelle Field, Maria I. Sierra, Sridhar Duvvuri, David L. Gray, Sokhom S. Pin, John J. Renger, David J. Stone
Recent studies have shown T cell cross-recognition of SARS-CoV-2 and common cold coronavirus spike proteins. However, the effect of SARS-CoV-2 vaccines on T cell responses to common cold coronaviruses remain unknown. In this study, we analyzed CD4+ T cell responses to spike peptides from SARS-CoV-2 and 3 common cold coronaviruses (HCoV-229E, HCoV-NL63, and HCoV-OC43) before and after study participants received Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) mRNA-based COVID-19 vaccines. Vaccine recipients made broad T cell responses to the SARS-CoV-2 spike protein and we identified 23 distinct targeted peptides in 9 participants including one peptide that was targeted by 6 individuals. Only 4 out of these 23 targeted peptides would potentially be affected by mutations in the UK (B.1.1.7) and South African (B.1.351) variants and CD4+ T cells from vaccine recipients recognized the 2 variant spike proteins as effectively as the spike protein from the ancestral virus. Interestingly, we saw a 3-fold increase in the CD4+ T cell responses to HCoV-NL63 spike peptides post-vaccination. Our results suggest that T cell responses elicited or enhanced by SARS-CoV-2 mRNA vaccines may be able to control SARS-CoV-2 variants and lead to cross-protection from some endemic coronaviruses.
Bezawit A. Woldemeskel, Caroline C. Garliss, Joel N. Blankson
Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of NFAT-dependent gene expression is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we utilized T cells from mice that express LckS59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either LckWT or LckS59A, it was ineffective in treating disease when the T cells expressed LckS59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in LckS59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8+ T cells and antigen-specific T:DC (dendritic cell) adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.
Shizuka Otsuka, Nicolas Melis, Matthias M. Gaida, Debjani Dutta, Roberto Weigert, Jonathan D. Ashwell
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