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Erik Henry Knelson, M.D.,Ph.D.

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Mentoring
Available: 11/02/20, Expires: 03/01/21

Clinical trials in thoracic cancers including malignant pleural mesothelioma (MPM) have demonstrated infrequent but promising responses to checkpoint immunotherapy, motivating strategies to promote antitumor immunity. Fundamental barriers include T-cell exclusion and inactivation in poorly inflamed “cold” tumors. Our lab and others have shown that cancer cells suppress cytokine release from viral-sensing pathways to evade immune rejection. Activating the stimulator of interferon genes (STING) pathway potently re-engages innate immunity, and injection of STING agonists causes T cell infiltration and tumor regression in multiple cancer models. While clinical trials of STING agonists have been disappointing, we have discovered therapeutic combinations to enhance antitumor immunity in select patient subsets. We have profiled STING expression in >300 archival specimens from patients with thoracic malignancies, observing uniformly high STING in MPM. Using fresh surgical specimens, we detect cytokine production from MPM tumor cells treated with STING agonists ex vivo in our organoid system that recapitulates the tumor-immune microenvironment. Tumor cell cytokine release leads to immune activation and cell death in ~50% of MPM tumors. We also observe robust cytokine release in four out of eleven immortalized MPM cell lines treated with STING agonists. It is unclear why certain cell lines and patient specimens respond to STING agonists, while others do not. The proposed question for the HMS scholarly project is what determines STING agonist response in MPM? Preliminary data in MPM cell lines and patient specimens show uniformly high STING expression and no correlation between histologic subtype of MPM and response to STING agonists. NF2 mutation status and cursory analysis of components of the innate immune cascade were also unrevealing, however the analysis is limited by our inexperience in bioinformatics. The dedicated bioinformatics consultant for the thoracic oncology research group has just taken a position in industry and we need assistance to complete this project for publication in 2021. We are looking for a medical student with previous experience in bioinformatics research to help in assembling a database of gene expression in MPM cell lines (CCLE contains a limited selection), as well as correlative analysis to generate a hypothesis as to why ~50% of patient specimens and cell lines respond to STING agonists. This project has direct clinical relevance, as phase 2 trials for STING agonists in MPM are underway and our lab has the ability to test patient specimens in functional treatment assays. Should the student wish to pursue hypothesis testing after the initial bioinformatics work (which can be conducted remotely during reduced lab availability), the mentor and senior PI are available and interested in supporting wet lab experiments to complete the project. Erik Knelson MD, PhD is a research instructor embedded within the Barbie lab at the Longwood Center, adjacent to the medical school main campus. This opportunity would involve close mentoring by experienced translational scientists seeking to develop novel cancer immunotherapeutics.


Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. F30CA168043 (KNELSON, ERIK H.) Apr 1, 2012 - Mar 31, 2014
    NIH/NCI
    The Role of Stroma-derived Soluble TbetaRIII in Neuroblastoma
    Role: Principal Investigator

Bibliographic
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Campisi M, Sundararaman SK, Shelton SE, Knelson EH, Mahadevan NR, Yoshida R, Tani T, Ivanova E, Cañadas I, Osaki T, Lee SWL, Thai T, Han S, Piel BP, Gilhooley S, Paweletz CP, Chiono V, Kamm RD, Kitajima S, Barbie DA. Tumor-Derived cGAMP Regulates Activation of the Vasculature. Front Immunol. 2020; 11:2090. PMID: 33013881.
    Citations:    Fields:    
  2. Puram RV, Erdil RM, Weber BN, Knelson EH, Van Beuningen AM, Wallwork R, Gilyard SN, Curtis BR, Ranganathan R, Leaf RK, Malhotra R. Thrombocytopenia and Thromboses in Myocardial Infarction Associated with Eptifibatide-Dependent Activating Antiplatelet Antibodies. Thromb Haemost. 2020 Jul; 120(7):1137-1141. PMID: 32483771.
    Citations:    Fields:    
  3. Kurppa KJ, Liu Y, To C, Zhang T, Fan M, Vajdi A, Knelson EH, Xie Y, Lim K, Cejas P, Portell A, Lizotte PH, Ficarro SB, Li S, Chen T, Haikala HM, Wang H, Bahcall M, Gao Y, Shalhout S, Boettcher S, Shin BH, Thai T, Wilkens MK, Tillgren ML, Mushajiang M, Xu M, Choi J, Bertram AA, Ebert BL, Beroukhim R, Bandopadhayay P, Awad MM, Gokhale PC, Kirschmeier PT, Marto JA, Camargo FD, Haq R, Paweletz CP, Wong KK, Barbie DA, Long HW, Gray NS, Jänne PA. Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway. Cancer Cell. 2020 01 13; 37(1):104-122.e12. PMID: 31935369.
    Citations: 7     Fields:    Translation:HumansAnimalsCells
  4. Ritter JL, Zhu Z, Thai TC, Mahadevan NR, Mertins P, Knelson EH, Piel BP, Han S, Jaffe JD, Carr SA, Barbie DA, Barbie TU. Phosphorylation of RAB7 by TBK1/IKKe Regulates Innate Immune Signaling in Triple-Negative Breast Cancer. Cancer Res. 2020 01 01; 80(1):44-56. PMID: 31662325.
    Citations:    Fields:    Translation:HumansCells
  5. Knelson EH, Vaidya A, Rawizza HE, Vaduganathan M, O'Gara PT. On the Cusp. N Engl J Med. 2017 05 25; 376(21):e45. PMID: 28538122.
    Citations:    Fields:    Translation:HumansCells
  6. Gaviglio AL, Knelson EH, Blobe GC. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation. FASEB J. 2017 05; 31(5):1903-1915. PMID: 28174207.
    Citations: 5     Fields:    Translation:HumansCells
  7. Knelson EH, Gaviglio AL, Nee JC, Starr MD, Nixon AB, Marcus SG, Blobe GC. Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth. J Clin Invest. 2014 Jul; 124(7):3016-31. PMID: 24937430.
    Citations: 10     Fields:    Translation:HumansAnimalsCells
  8. Knelson EH, Nee JC, Blobe GC. Heparan sulfate signaling in cancer. Trends Biochem Sci. 2014 Jun; 39(6):277-88. PMID: 24755488.
    Citations: 41     Fields:    Translation:HumansAnimalsCells
  9. Knelson EH, Gaviglio AL, Tewari AK, Armstrong MB, Mythreye K, Blobe GC. Type III TGF-ß receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma. J Clin Invest. 2013 Nov; 123(11):4786-98. PMID: 24216509.
    Citations: 14     Fields:    Translation:HumansCells
  10. Oh SY, Knelson EH, Blobe GC, Mythreye K. The type III TGFß receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. Biochem J. 2013 Aug 15; 454(1):79-89. PMID: 23750457.
    Citations: 5     Fields:    Translation:HumansAnimalsCells
  11. Van Mater D, Knelson EH, Kaiser-Rogers KA, Armstrong MB. Neuroblastoma in a pediatric patient with a microduplication of 2p involving the MYCN locus. . 2013 Mar; 161A(3):605-10. PMID: 23401364.
    Citations: 2     Translation:HumansCells
  12. Mythreye K, Knelson EH, Gatza CE, Gatza ML, Blobe GC. TßRIII/ß-arrestin2 regulates integrin a5ß1 trafficking, function, and localization in epithelial cells. Oncogene. 2013 Mar 14; 32(11):1416-27. PMID: 22562249.
    Citations: 13     Fields:    Translation:HumansAnimalsCells
  13. Ramirez JJ, Poulton WE, Knelson E, Barton C, King MA, Klein RL. Focal expression of mutated tau in entorhinal cortex neurons of rats impairs spatial working memory. Behav Brain Res. 2011 Jan 01; 216(1):332-40. PMID: 20727915.
    Citations: 9     Fields:    Translation:AnimalsCells
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.