Anti-CTLA-4 + anti-PD-1/PD-L1 combination is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAE). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrated myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFNγ–dependent mechanism. Targeting the HIF-1α-PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes (TILs) and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated cancer immunotherapeutic effects of anti-CTLA-4 therapy with efficacy comparable to anti-CTLA-4+anti-PD-1 antibodies. However, while anti-PD-1 exacerbated irAE triggered by Ipilimumab, echinomycin protected mice against irAE by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1:PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment (TME) to achieve safer and more effective immunotherapy.
Christopher M. Bailey, Yan Liu, Mingyue Liu, Xuexiang Du, Martin Devenport, Pan Zheng, Yang Liu, Yin Wang
Extracellular proteolysis is frequently dysregulated in disease and can generate proteoforms with unique neoepitopes not found in healthy tissue. Here, we demonstrate that Abs that selectively recognize a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) could enable more effective and safer treatments for solid tumors. CDCP1 is highly overexpressed in RAS-driven cancers, and its ectodomain is cleaved by extracellular proteases. Biochemical, biophysical, and structural characterization revealed that the 2 cleaved fragments of CDCP1 remain tightly associated with minimal proteolysis-induced conformational change. Using differential phage display, we generated recombinant Abs that are exquisitely selective to cleaved CDCP1 with no detectable binding to the uncleaved form. These Abs potently targeted cleaved CDCP1-expressing cancer cells as an Ab-drug conjugate, an Ab-radionuclide conjugate, and a bispecific T cell engager. In a syngeneic pancreatic tumor model, these cleaved-specific Abs showed tumor-specific localization and antitumor activity with superior safety profiles compared with a pan-CDCP1 approach. Targeting proteolytic neoepitopes could provide an orthogonal “AND” gate for improving the therapeutic index.
Shion A. Lim, Jie Zhou, Alexander J. Martinko, Yung-Hua Wang, Ekaterina V. Filippova, Veronica Steri, Donghui Wang, Soumya G. Remesh, Jia Liu, Byron Hann, Anthony A. Kossiakoff, Michael J. Evans, Kevin K. Leung, James A. Wells
Nigel S. Paneth, Michael J. Joyner, Arturo Casadevall
Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T cells (Tconv, CD45RChigh), their precursors and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs, CD45RClow/-). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation but its potential has not been examined in autoimmune diseases. APECED is a rare genetic syndrome caused by loss-of-function mutations of the key central tolerance mediator, autoimmune regulator (AIRE) leading to abnormal auto-reactive T cell responses and autoantibodies production. Herein, we showed that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective both as prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RChigh T cells, inhibited CD45RChigh B cells, and restored the Treg/Tconv ratio and the altered Tregs transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells and lesioned organs from APECED patients were infiltrated by CD45RChigh cells. Our observations highlight the potential role for CD45RChigh cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.
Marine Besnard, Céline Sérazin, Jason Ossart, Anne Moreau, Nadège Vimond, Léa Flippe, Hanna Sein, Grace A. Smith, Stefania Pittaluga, Elise M.N. Ferré, Claire Usal, Ignacio Anegon, Annamari Ranki, Michail S. Lionakis, Pärt Peterson, Carole Guillonneau
BACKGROUND. Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies have shown that excessive TGF-β signaling is a driver of pathogenesis in OI. Here, we evaluated TGF-β signaling in children with OI and translated this discovery by conducting a phase 1 clinical trial of TGF-β inhibition in adults with OI. METHODS. Histology and RNASeq were performed on bones obtained from children affected (n=10) and unaffected (n=4) by OI. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify key dysregulated pathways. Reverse-phase protein array (RPPA), Western blot (WB), and Immunohistochemistry (IHC) were performed to evaluate changes at the protein level. A phase 1 study with a single administration of fresolimumab, a pan-anti-TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects of fresolimumab on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS. OI bone demonstrated woven structure, increased osteocyte density, high turnover, and reduced bone maturation. SMAD phosphorylation was the most significantly up-regulated GO molecular event. GSEA identified TGF-β pathway as top activated signaling pathway in OI. IPA showed that TGF-β was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increase in LS aBMD in participants with OI type IV, while those with more severe OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSIONS. Our data confirm that TGF-β signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION. NCT03064074 FUNDING. This work was supported by the Brittle Bone Disorders Consortium (BBDC) (U54AR068069). The BBDC is a part of the National Center for Advancing Translational Science’s (NCATS’) RDCRN. The BBDC is funded through a collaboration between the Office of Rare Disease Research (ORDR) of NCATS, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The BBDC was also supported by the OI Foundation. The work was supported by The Clinical Translational Core of BCM IDDRC (P50HD103555) from the Eunice Kennedy Shriver NICHD. Funding from the USDA/ARS under Cooperative Agreement No. 58-6250-6-001 also facilitated analysis for the study procedures. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The study was supported by a research agreement with Sanofi Genzyme.
I-Wen Song, Sandesh C.S. Nagamani, Dianne Nguyen, Ingo Grafe, Vernon Reid Sutton, Francis H. Gannon, Elda Munivez, Ming-Ming Jiang, Alyssa Tran, Maegen Wallace, Paul Esposito, Salma Musaad, Elizabeth Strudthoff, Sharon McGuire, Michele Thornton, Vinitha Shenava, Scott Rosenfeld, Roman Shypailo, Eric Orwoll, Brendan Lee
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine depleting agent ADI-PEG20 in a non-arginine auxotrophic cellular background (Arginine Succinate Synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response with extended disease-free survival in an orthotopic immune competent model of GBM with no significant toxicity. ADI-PEG20 not only enhances the cellular sensitivity of Arginine succinate synthetase 1 positive GBM to ionising radiation by elevated production of nitric oxide (NO) and hence generation of cytotoxic peroxynitrites, but also promotes glioma-associated macrophages/microglia infiltration into tumors and turns their classical anti-inflammatory (pro-tumor) phenotype into a pro-inflammatory (anti-tumor) phenotype. Our results provide an effective, well-tolerated and simple strategy to improve GBM treatment which merits consideration for early evaluation in clinical trials.
Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake J. Symington, Chad C. Quarles, Deborah R. Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G. Tzakos, Timothy Crook, Kevin O'Neill, Adrienne C. Scheck, Jose Luis Venero, Nelofer Syed
Immune checkpoint blockade (ICB) therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to the emergence of immune-refractory tumors that disrupt the amplification of anti-tumor immunity. Therefore, identifying clinically available targets that restrict anti-tumor immunity is required to develop potential combination strategies. Here, using the transcriptome data of cancer patients treated with programmed cell death protein-1 (PD-1) therapy, and newly-established mouse preclinical anti-PD-1 therapy-refractory models, we identified NANOG as a novel factor restricting the amplification of anti-tumor immunity cycle, thereby contributing to the immune-refractory feature of the tumor microenvironment (TME). Mechanistically, NANOG induced insufficient T cell infiltration and resistance to CTL-mediated killing via the HDAC1-dependent regulation of CXCL10 and MCL1, respectively. Importantly, HDAC1 inhibition using an actionable agent sensitized NANOGhigh immune-refractory tumors to PD-1 blockade by reinvigorating the anti-tumor immunity cycle. Thus, our findings implicate the NANOG/HDAC1 axis as a central molecular target for controlling immune-refractory tumors and provide a rationale for combining HDAC inhibitors to reverse the refractoriness of tumors to ICB therapy.
Se Jin Oh, Hyo-Jung Lee, Kwon-Ho Song, Suyeon Kim, Eunho Cho, Jaeyoon Lee, Marcus W. Bosenberg, Tae Woo Kim
BACKGROUND. Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined. METHODS. Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT. RESULTS. We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product. CONCLUSIONS. These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells. FUNDING. NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.
Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup
The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine–regulated transfer RNA–derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.
Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng
Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/α-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIs-associated weight gain this study proposes a therapeutic strategy to counter it.
Maria Jose Ortuno, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy
No posts were found with this tag.