Go to JCI Insight
Jci spelled out white on transparent.20160208
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • Fibrosis (Jan 2018)
    • Glia and Neurodegeneration (Sep 2017)
    • Transplantation (Jun 2017)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

Jci only white

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication

Oncology

  • 805 Articles
  • 14 Posts
  • ←
  • 1
  • 2
  • 3
  • …
  • 80
  • 81
  • →
Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor
Gerardo A. Vitiello, … , Shan Zeng, Ronald P. DeMatteo
Gerardo A. Vitiello, … , Shan Zeng, Ronald P. DeMatteo
Published February 14, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI124108.
View: Text | PDF

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor

  • Text
  • PDF
Abstract

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.

Authors

Gerardo A. Vitiello, Timothy G. Bowler, Mengyuan Liu, Benjamin D. Medina, Jennifer Q. Zhang, Nesteene J. Param, Jennifer K. Loo, Rachel L. Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, Ronald P. DeMatteo

×

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma
Alex B. Blair, … , Victoria Kim, Lei Zheng
Alex B. Blair, … , Victoria Kim, Lei Zheng
Published February 12, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI124077.
View: Text | PDF

IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma

  • Text
  • PDF
Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents an immune quiescent tumor that is resistant to immune checkpoint inhibitors. Previously, our group has shown that a GM-CSF secreting allogenic pancreatic tumor cell vaccine (GVAX), may prime the tumor microenvironment by inducing intratumoral T-cell infiltration. Here, we show that untreated PDACs express minimal indoleamine-2, 3-dioxygenase (IDO1); however, GVAX therapy induced IDO1 expression on tumor epithelia as well as vaccine-induced tertiary lymphoid aggregates. IDO1 expression plays a role in regulating the polarization of Th1, Th17, and possibly T-regulatory cells in PDAC tumors. IDO1 inhibitor enhanced anti-tumor efficacy of GVAX in a murine model of PDACs. The combination of vaccine and IDO1 inhibitor enhanced intratumoral T-cell infiltration and function, but adding anti-PD-L1 antibody to the combination did not offer further synergy and in fact may have a negative interaction decreasing the number of intratumoral effector T-cells. Additionally, IDO1 inhibitor in the presence of vaccine therapy, did not significantly modulate intratumoral myeloid derived suppressor cells quantitatively, but diminished their suppressive effect on CD8+ proliferation. Our study thus supports the combination of IDO1 inhibitor and vaccine therapy, however, does not support the combination of IDO1 inhibitor and anti-PD-1/PD-L1 antibody for T cell-inflamed tumors such as PDACs treated with vaccine therapy.

Authors

Alex B. Blair, Jennifer Kleponis, Dwayne L. Thomas II, Stephen T. Muth, Adrian G. Murphy, Victoria Kim, Lei Zheng

×

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers
Tina Gruosso, … , Benjamin Haibe-Kains, Morag Park
Tina Gruosso, … , Benjamin Haibe-Kains, Morag Park
Published February 12, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI96313.
View: Text | PDF

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers

  • Text
  • PDF
Abstract

Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC with implications for current therapies, including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+ CD8+ T cells, a type I interferon signature, elevated expression of multiple immune inhibitory molecules, including IDO, PD-L1, and good outcome. An “immune-cold” microenvironment with absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma and poor outcome. A distinct poor outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1 and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes stratified TNBC, predicting outcome and identifying potential therapeutic targets for TNBC.

Authors

Tina Gruosso, Mathieu Gigoux, Venkata Satya Kumar Manem, Nicholas Bertos, Dongmei Zuo, Irina Perlitch, Sadiq Mehdi Ismail Saleh, Hong Zhao, Margarita Souleimanova, Radia Marie Johnson, Anne Monette, Valentina Munoz Ramos, Michael Trevor Hallett, John Stagg, Réjean Lapointe, Atilla Omeroglu, Sarkis Meterissian, Laurence Buisseret, Gert Van den Eynden, Roberto Salgado, Marie-Christine Guiot, Benjamin Haibe-Kains, Morag Park

×

Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms
Simona Stivala, … , Ross L. Levine, Sara C. Meyer
Simona Stivala, … , Ross L. Levine, Sara C. Meyer
Published February 7, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI98785.
View: Text | PDF

Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms

  • Text
  • PDF
Abstract

Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK kinase inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling suggesting cell extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK kinase inhibition. PDGF-BB maintained ERK activation in presence of ruxolitinib consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.

Authors

Simona Stivala, Tamara Codilupi, Sime Brkic, Anne Baerenwaldt, Nilabh Ghosh, Hui Hao-Shen, Stephan Dirnhofer, Matthias S. Dettmer, Cedric Simillion, Beat A. Kaufmann, Sophia Chiu, Matthew D. Keller, Maria Kleppe, Morgane Hilpert, Andreas S. Buser, Jakob R. Passweg, Thomas Radimerski, Radek C. Skoda, Ross L. Levine, Sara C. Meyer

×

Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and MTOR
Fangyang Wang, … , Daniel J. Klionsky, Sami N. Malek
Fangyang Wang, … , Daniel J. Klionsky, Sami N. Malek
Published February 5, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI98288.
View: Text | PDF

Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and MTOR

  • Text
  • PDF
Abstract

The discovery of recurrent mutations in subunits of the vacuolar-type H+-translocating ATPase (v-ATPase) in follicular lymphoma (FL) highlights a role for the amino acid- and energy-sensing pathway to MTOR in the pathogenesis of this disease. Here, through the use of complementary experimental approaches involving mammalian cells and Saccharomyces cerevisiae, we have demonstrated that mutations in the v-ATPase subunit ATP6V1B2/Vma2 activate autophagic flux and maintain MTOR/Tor in an active state. Engineered lymphoma cell lines and primary follicular lymphoma B cells (FL B cells) carrying mutated ATP6V1B2 demonstrated a remarkable ability to survive low leucine concentrations. The treatment of primary FL B cells with inhibitors of autophagy uncovered an addiction for survival for FL B cells harboring ATP6V1B2 mutants. These data support mutational activation of autophagic flux by recurrent hotspot mutations in ATP6V1B2 as an adaptive mechanism in FL pathogenesis and as a new possible therapeutically targetable pathway.

Authors

Fangyang Wang, Damián Gatica, Zhang Xiao Ying, Luke F. Peterson, Peter K. Kim, Denzil Bernard, Kamlai Saiya-Cork, Shaomeng Wang, Mark S. Kaminski, Alfred E. Chang, Tycel Phillips, Daniel J. Klionsky, Sami N. Malek

×

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth
Shaikamjad Umesalma, … , Frederick W. Quelle, Dawn E. Quelle
Shaikamjad Umesalma, … , Frederick W. Quelle, Dawn E. Quelle
Published February 5, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI123049.
View: Text | PDF

RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth

  • Text
  • PDF
Abstract

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A depleted cells resulted from increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A depleted cells whereas PP2A reactivation using a specific small molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. This work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Authors

Shaikamjad Umesalma, Courtney A. Kaemmer, Jordan L. Kohlmeyer, Blake L. Letney, Angela M. Schab, Jacqueline A. Reilly, Ryan M. Sheehy, Jussara Hagen, Nitija Tiwari, Fenghuang Zhan, Mariah R. Leidinger, Thomas M. O'Dorisio, Joseph S. Dillon, Ronald A. Merrill, David K. Meyerholz, Abbey L. Perl, Bart J. Brown, Terry A. Braun, Aaron T. Scott, Timothy Ginader, Agshin F. Taghiyev, Gideon K. Zamba, James R. Howe, Stefan Strack, Andrew M. Bellizzi, Goutham Narla, Benjamin W. Darbro, Frederick W. Quelle, Dawn E. Quelle

×

Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers
Parisa Malekzadeh, … , Steven A. Rosenberg, Drew C. Deniger
Parisa Malekzadeh, … , Steven A. Rosenberg, Drew C. Deniger
Published February 4, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI123791.
View: Text | PDF

Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers

  • Text
  • PDF
Abstract

Authors

Parisa Malekzadeh, Anna Pasetto, Paul F. Robbins, Maria R. Parkhurst, Biman C. Paria, Li Jia, Jared J. Gartner, Victoria Hill, Zhiya Yu, Nicholas P. Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert P.T. Somerville, Steven A. Rosenberg, Drew C. Deniger

×

Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcystosine loss in renal cell carcinoma
Niraj Shenoy, … , Yiyu Zou, Amit Verma
Niraj Shenoy, … , Yiyu Zou, Amit Verma
Published January 31, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI98747.
View: Text | PDF

Ascorbic acid–induced TET activation mitigates adverse hydroxymethylcystosine loss in renal cell carcinoma

  • Text
  • PDF
Abstract

Although ccRCC has been shown to have widespread aberrant cytosine methylation and loss of hydroxymethylation (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was significantly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression free survival after resection of non-metastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of TET enzymes, but by their functional inactivation by l-2-hydroxyglutarate (L2HG) that was overexpressed due to the deletion and under-expression of l-2-hydroxyglutarate dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high dose AA in ccRCC.

Authors

Niraj Shenoy, Tushar D. Bhagat, John C. Cheville, Christine Lohse, Sanchari Bhattacharyya, Alexander Tischer, Venkata Machha, Shanisha Gordon-Mitchell, Gaurav S. Choudhary, Li-Fan Wong, LouAnn Gross, Emily Ressegue, Bradley C. Leibovich, Stephen A. Boorjian, Ulrich Steidl, Xiaosheng Wu, Kith Pradhan, Benjamin Gartrell, Beamon Agarwal, Lance Pagliaro, Masako Suzuki, John M. Greally, Dinesh Rakheja, R. Houston Thompson, Katalin Susztak, Thomas Witzig, Yiyu Zou, Amit Verma

×

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy
Tori N. Yamamoto, … , Nicholas P. Restifo, Christopher A. Klebanoff
Tori N. Yamamoto, … , Nicholas P. Restifo, Christopher A. Klebanoff
Published January 29, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI121491.
View: Text | PDF

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy

  • Text
  • PDF
Abstract

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand/receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and anti-tumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells co-engineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior anti-tumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.

Authors

Tori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, Christopher A. Klebanoff

×

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Gaoxiang Zhao, … , Daming Gao, Hongbin Ji
Published January 28, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI122779.
View: Text | PDF

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1

  • Text
  • PDF
Abstract

Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1–/– Trp53–/– SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin β1, which stabilized integrin β1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.

Authors

Gaoxiang Zhao, Liyan Gong, Dan Su, Yujuan Jin, Chenchen Guo, Meiting Yue, Shun Yao, Zhen Qin, Yi Ye, Ying Tang, Qibiao Wu, Jian Zhang, Binghai Cui, Qiurong Ding, Hsinyi Huang, Liang Hu, Yuting Chen, Peiyuan Zhang, Guohong Hu, Luonan Chen, Kwok-Kin Wong, Daming Gao, Hongbin Ji

×
  • ←
  • 1
  • 2
  • 3
  • …
  • 80
  • 81
  • →
  • ←
  • 1
  • 2
  • →
Attack of the WNT inducing macrophages
Luke Boulter and colleagues reveal that WNT ligand-secreting macrophages promote cholangiocarcinoma proliferation….
Published February 17, 2015
Scientific Show StopperOncology
Thumb 76452 img4

Metabolic reprogramming in prostate cancer
Subhamoy Dasgupta and colleagues reveal that steroid receptor coactivator 2 mediates metabolic reprogramming that supports growth and survival of prostate cancer cells….
Published February 9, 2015
Scientific Show StopperOncology
Thumb 76029 pca cells with lipids  1

NOTCH keeps bladder cancer at bay
Antonio Maraver, Pablo Fernandez-Marcos, and colleagues demonstrate the NOTCH serves as a tumor suppressor in the bladder…
Published January 9, 2015
Scientific Show StopperOncology
Thumb serrano sss

T cell signals substitute for EBV oncoprotein
Shi-Dong Ma and colleagues develop a human cord blood-based model of EBV-induced B cell lymphoma to evaluate the requirement of EBV oncoprotein LMP1 in pathogenesis…
Published December 8, 2014
Scientific Show StopperOncology
Thumb 12.8.14
  • ←
  • 1
  • 2
  • →
Advertisement
Follow JCI: Facebook logo white Twitter logo v2 Rss icon
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts