Faculty Summaries
Siddharth Balachandran, PhD
Siddharth Balachandran, PhD
Associate Professor
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
Fax: 215-728-3574
Office: R224
Cytokine Signaling in Host Innate Immune and Anti-Tumor Responses

A key component of mammalian immunity against viruses and cancer is a family of cytokines called the interferons (IFNs, so called because they ‘interfere’ with virus replication). The IFNs are classified into two groups, type I and type II. Type I (α/β) IFNs are produced by most cell types in response to viral infection, whereas type II IFN (called IFN-γ) is made by a select subset of immune system cells and is not virus inducible.

Type I IFNs (e.g.IFN-α2) were approved by the Food & Drug Administration (FDA) in 1986 as the first commercial anticancer biotherapeutic, and are currently employed in the treatment of over twenty human cancers. It is thought that the IFNs exert their antitumor effects by modulation and reactivation of the immune response to the tumor and/or by direct tumoricidal activity, but the underlying mechanisms remain poorly described. In the years preceding their approval by the FDA, the IFNs were touted as a potential ‘silver bullet’ cure for many forms of cancer, even making the cover of Time magazine in 1980. Unfortunately, these cytokines have, in recent years, fallen out of favor with many oncologists because of their very unpleasant side-effects. Nevertheless, IFNs continue to be used in the clinic and provide spectacular cures of several highly malignant cancers (such as AIDS-associated lymphomas and metastatic renal cell carcinoma), highlighting their Janus-faced nature.

The primary problem with IFN therapy is that IFN is, of course, also a potent antiviral cytokine and triggers a powerful innate immune response in the patient, whose body responds to systemic therapeutic IFN as it would to an acute viremia. Efforts are currently underway to target IFN delivery to the tumor site (particularly for solid tumors), but an equally compelling avenue of research is to determine the mechanism(s) by which IFNs selectively mediate their cytotoxic effects, and exploit these mechanisms to make IFN a more potent therapeutic (and thereby reduce its effective dose by, hopefully, at least one order of magnitude). Our laboratory is therefore very interested in the molecular processes by which IFNs specifically exert their anti-proliferative effects. We have recently identified novel pathways by which the IFNs induce cell survival and death and are currently elucidating these mechanisms.

Another area of research in the laboratory is to understand how type I IFNs and other antiviral genes are induced after virus infection. In a current model, virus replication in the cytosol activates at least three classes of transcription factors to induce primary antiviral genes (including type I IFNs). Of these factors, we are particularly interested in NF-κB, and are currently defining its mechanism of activation and role in antiviral responses.

Description of research projects
Selected Publications
  1. Wang X, Wang J, Hopewell EL, Hussain S, Garcia-Sastre A, Balachandran S, Beg AA. Differential requirement for the IKKb/NF-kB signaling module in mediating TLR versus RLR-induced transcriptional responses. J Immunol. (In press).
  2. Haugh KA, Shalginskikh N, Nogusa S, Skalka AM, Katz RA, Balachandran S. The interferon-inducible antiviral protein Daxx is not essential for interferon-mediated protection against avian sarcoma virus. Virology J. 2014;11:100. PubMed
  3. Kaiser WJ, Daley-Bauer LP, Thapa RJ, Mandal P, Berger SB, Huang C, Sundararajan A, Guo H, Roback L, Speck SH, Bertin J, Gough PJ, Balachandran S, Mocarski ES. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci USA. 2014;111:7753-8. PubMed
  4. Peri S, Devarajan K, Wang DH, Knudson AG, Balachandran S. Meta-analysis identifies NF-κB as a therapeutic target in renal cancer. PLoS One. 2013;8:e76746. PubMed
  5. Thapa RJ, Nogusa S, Chen P, Maki JL, Lerro A, Andrake, M, Rall GF, Degterev A, Balachandran S. Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Proc Natl Acad Sci USA. 2013;110:e3109-18. Highlighted in Nature Immunology (August 2013) and recommended to Faculty of 1000. PubMed
  6. Thapa RJ, Chen P, Cheung M, Nogusa S, Pei J, Peri S, Testa JR, Balachandran S. NF-κB inhibition by bortezomib permits interferon-γ-activated RIP1 kinase-dependent necrosis in renal cell carcinoma. Mol Cancer Ther. 2013;May 8 [Epub ahead of print]. PubMed
  7. Chen P, Nogusa S, Thapa RJ, Simmons H, Shaller C, Peri S, Adams GR, Balachandran S. Anti-CD70 immunocytokines for exploitation of interferon-γ-induced programmed necrosis in renal cell carcinoma. PLoS One 2013;8:e61446. PubMed
  8. Balachandran S, Adams GP. Interferon-γ-induced necrosis: an anti-tumor biotherapeutic perspective. J Interferon Cytokine Res. 2013;33:171-80. PubMed
  9. Balachandran S, Beg AA. Defining roles for NF-κB in antivirus responses: revisiting the interferon-β enhanceosome paradigm. PLoS Pathog. 2011;7:e1002165. PubMed
  10. Thapa RJ, Basagoudanavar S, Nogusa S, Irrinki K, Mallilankaraman K, Slifker MJ, Beg AA, Madesh M, Balachandran S. NF-κB protects cells from interferon-γ-induced RIP1-dependent necroptosis. Mol Cell Biol. 2011;31:2934-46. PubMed
  11. Basagoudanavar SH, Thapa RJ, Nogusa S, Wang J, Beg AA, Balachandran S. Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses. J Virol. 2011;85:2599-610. PubMed
  12. Balachandran S, Thomas E, Barber GN. A FADD-dependent innate immune mechanism in mammalian cells. Nature. 2004;432:401-5. PubMed
  13. Balachandran S, Barber GN. Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell. 2004;5:51-65. PubMed
  14. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity. 2000;13:129-41. PubMed
  15. Balachandran S, Kim CN, Yeh WC, Mak TW, Bhalla K, Barber GN. Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J. 1998;17:6888-902. PubMed
All publications