Srinivas Nagaraj, PhD

Associations

• Immuno-Oncology Program

One of the major mechanisms of tumor progression is the inability of the host system to develop an effective immune response. Indeed, accumulating evidence has now shown that a population of cells with suppressive activity, known as myeloid derived suppressor cells contributes to the failure of the failure of the immune system to tackle the tumor cells and also towards the low efficacy of cancer vaccines.   The recognition of that the immune suppression plays a crucial role in promoting tumor progression and contributes to the failure has resulted in a paradigm shift regarding approaches to cancer immunotherapy.  Successful cancer therapy will be successful if strategies involve either the differentation or elimination of suppressive cells compared to direct cancer therapy trying to eliminate tumor cells which has proved less futile.  MDSC are a heteregenous mixture of precursors of dendritic cells, macrophages and monocytes.  One of the most plausible ideas will be differentiating these cells in to their mature counterparts which not only lack suppressive function but will also boost the immune response.  Based on our recent work in cancer and nanotherapeutics we hypothesise the development and application of a multifunctional nanoparticles  to effectively promote the differentiation of  MDSCs in cancer. The respiratory system is continuously exposed to a barrage of potentially harmful external factors. Lipopolysaccharide (LPS), a component of the bacterial cell wall, is one of the prevalent contaminant in air, which brings about inflammation.  Inflammation reflects a well-orchestrated cytokine and cellular events from an acute to a chronic stage.  A constant or experimental high dose of exposure to LPS results in dampening the immune response. Chronic inflammation is accompanied by impaired T-cell immunity. It is well known that most of the lung diseases have chronic exposure to significant high levels of LPS. This results in chronic airway inflammation leading to lung tissue damage and impaired T cell immunity.  Inability of the host system to mount an effective immune response is one of the major factors responsible for tissue injury. We know that a heterogeneous group of myeloid cells termed myeloid derived suppressor cells (MDSC) accumulate in almost all pathological conditions, which elicit an inflammatory signal.  The exact role played by these cells in inflammation and their role played in inducing T cell abnormality is not known. Identifying the nature and function of these cells in T cell suppression would contribute to new strategies in controlling airway inflammation.  The overall goals of this study are to examine   the nature of MDSC in airway inflammation and their role in T cell tolerance.    The above two projects may provide a link between inflammation and cancer.  

• Wang D, Yu Y, Haarberg K, Fu J, Kaosaard K, Nagaraj S, Anasetti C, Gabrilovich D, Yu XZ. Dynamic change and impact of myeloid-derived suppressor cells in allogeneic bone marrow transplantation in mice. Biol Blood Marrow Tr. 2013 May.19(5):692-702. Pubmedid: 23376089. Pmcid: PMC4011929.
• Mallela J, Ravi S, Jean Louis F, Mulaney B, Cheung M, Sree Garapati U, Chinnasamy V, Wang C, Nagaraj S, Mohapatra SS, Mohapatra S. Natriuretic peptide receptor A signaling regulates stem cell recruitment and angiogenesis: a model to study linkage between inflammation and tumorigenesis. Stem Cells. 2013 Jul.31(7):1321-1329. Pubmedid: 23533187. Pmcid: PMC3982194.
• Nagaraj S, Youn JI, Gabrilovich DI. Reciprocal relationship between myeloid-derived suppressor cells and T cells. J Immunol. 2013 Jul.191(1):17-23. Pubmedid: 23794702. Pmcid: PMC3694485.
• Nelson A, Nair S, Nagaraj S. CD4(+) T cells suppress immune response to cancer: novel targets for antitumor efforts. Expert Rev Clin Immunol. 2012 Jul.8(5):401-403. Pubmedid: 22882213.
• Brar T, Nagaraj S, Mohapatra S. Microbes and asthma: the missing cellular and molecular links. Curr Opin Pulm Med. 2012 Jan.18(1):14-22. Pubmedid: 22113000. Pmcid: PMC3532043.
• Nagaraj S, Nelson A, Youn JI, Cheng P, Quiceno D, Gabrilovich DI. Antigen-specific CD4(+) T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res. 2012 Feb.72(4):928-938. Pubmedid: 22237629. Pmcid: PMC4062074.
• Nagaraj S, Gabrilovich DI. Regulation of suppressive function of myeloid-derived suppressor cells by CD4+ T cells. Semin Cancer Biol. 2012 Aug.22(4):282-288. Pubmedid: 22313876. Pmcid: PMC3349790.
• Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010 Mar.16(6):1812-1823. Pubmedid: 20215551. Pmcid: PMC2840181.
• Nagaraj S, Schrum AG, Cho HI, Celis E, Gabrilovich DI. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J Immunol. 2010 Mar.184(6):3106-3116. Pubmedid: 20142361. Pmcid: PMC2832724.
• Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010 Jul.16(4):348-353. Pubmedid: 20693846.
• Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, Corzo A, Cho HI, Celis E, Lennox B, Knight SC, Padhya T, McCaffrey TV, McCaffrey JC, Antonia S, Fishman M, Ferris RL, Kagan VE, Gabrilovich DI. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010 Aug.16(8):880-886. Pubmedid: 20622859. Pmcid: PMC2917488.
• Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI. Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. J Clin Invest. 2010 Apr.120(4):1111-1124. Pubmedid: 20234093. Pmcid: PMC2846048.
• Nagaraj S, Collazo M, Corzo CA, Youn JI, Ortiz M, Quiceno D, Gabrilovich DI. Regulatory myeloid suppressor cells in health and disease. Cancer Res. 2009 Oct.69(19):7503-7506. Pubmedid: 19752086. Pmcid: PMC2756310.
• Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar.9(3):162-174. Pubmedid: 19197294. Pmcid: PMC2828349.
• Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, Ortiz M, Nacken W, Sorg C, Vogl T, Roth J, Gabrilovich DI. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008 Sep.205(10):2235-2249. Pubmedid: 18809714. Pmcid: PMC2556797.
• Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008 Oct.181(8):5791-5802. Pubmedid: 18832739. Pmcid: PMC2575748.
• Ziske C, Tiemann K, Schmidt T, Nagaraj S, Märten A, Schmitz V, Clarenbach R, Sauerbruch T, Schmidt-Wolf IG. Real-time high-resolution compound imaging allows percutaneous initiation and surveillance in an orthotopic murine pancreatic cancer model. Pancreas. 2008 Mar.36(2):146-152. Pubmedid: 18376305.
• Nagaraj S, Gabrilovich D. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 2008 Apr.68(8):2561-2563. Pubmedid: 18413722.
• Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O'Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL. MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med. 2007 Jun.204(6):1463-1474. Pubmedid: 17548519. Pmcid: PMC2118626.
• Herber DL, Nagaraj S, Djeu JY, Gabrilovich DI. Mechanism and therapeutic reversal of immune suppression in cancer. Cancer Res. 2007 Jun.67(11):5067-5069. Pubmedid: 17545581. Pmcid: PMC1976287.
• Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber D, Schneck J, Gabrilovich DI. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med. 2007 Jul.13(7):828-835. Pubmedid: 17603493. Pmcid: PMC2135607.
• Nagaraj S, Gabrilovich D. Myeloid-derived suppressor cells. Adv Exp Med Biol. 2007.601:213-223. Pubmedid: 17713008.
• Nefedova Y, Nagaraj S, Rosenbauer A, Muro-Cacho C, Sebti SM, Gabrilovich DI. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacologic-selective inhibition of the janus-activated kinase 2/signal transducers and activators of transcription 3 pathway. Cancer Res. 2005 Oct.65(20):9525-9535. Pubmedid: 16230418. Pmcid: PMC1351362.
• Kusmartsev S, Nagaraj S, Gabrilovich DI. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol. 2005 Oct.175(7):4583-4592. Pubmedid: 16177103. Pmcid: PMC1350970.
• Nagaraj S, Ziske C, Schmidt-Wolf IG. Human cytokine-induced killer cells have enhanced in vitro cytolytic activity via non-viral interleukin-2 gene transfer. Genet Vaccines Ther. 2004.2:12. Pubmedid: 15329148. Pmcid: PMC516021.
• Nagaraj S, Pisarev V, Kinarsky L, Sherman S, Muro-Cacho C, Altieri DC, Gabrilovich DI. Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors. J Immunother. 30(2):169-179. Pubmedid: 17471164.