Rupali Das, Ph.D.
Several recurrent or refractory cancers are often resistant to standard chemotherapies and patients demonstrate poor tolerance of treatment due to organ dysfunction and increased susceptibility to infection. To improve the outcomes for patients with difficult-to-manage cancers, my laboratory will develop alternative therapeutic approaches that capitalize on the anti-tumor functions of invariant natural killer T (iNKT) cells, innate-type lipid-reactive T lymphocytes that express a common or "invariant" T cell receptor (iTCR) that confers specificity for glycolipid antigens presented by the MHC class 1-like molecule CD1d. Following iTCR engagement, iNKT cells rapidly secrete TH1 and TH2-type cytokines and up-regulate the expression of co-stimulatory molecules. Via these mechanisms, iNKT cells induce dendritic cell (DC) maturation and enhance the functions of numerous other types of immune cells including NK, T and B cells. As such, iNKT cells participate in many aspects of host immunity, including protection against cancer. iNKT cells mediate their anti-tumor activity via multiple mechanisms. Their dominant mode of action involves the transactivation of other cytolytic effectors such as CD8+T and NK cells. In addition to their immune-stimulatory functions, iNKT cells also function as cytotoxic effectors. Maximal tumor-directed iNKT cell responses require tumor cell expression of CD1d. However, many tumors down-regulate CD1d and thus evade iNKT cell recognition. To circumvent this critical barrier, we will use innovative approaches to direct iNKT cells to the site of cancers in a tumor antigen-specific yet CD1d-independent manner. These studies are significant because they will facilitate a better understanding of how to harness the anti-tumor activities of iNKT cells in a clinically relevant manner to improve the cure rate for people with cancer.
Efforts are underway to manipulate iNKT cell functions therapeutically for cancer and other diseases. However, before these efforts can be fully realized, it is necessary to define how iNKT cells recognize and respond to targets, including malignant or infected cells. It has been recognized for over a decade that iNKT cells kill activated, infected or malignant cells. Despite this fact, little is known about the signals that promote TCR-induced iNKT cell killing or the factors that support functional interactions between iNKT cells and their tumor targets. Furthermore, there exist almost no data regarding the kinetics and molecular organization of the immunologic synapse (IS) that is formed upon contact of iNKT cells with the target cells. To provide insights into these fundamental processes, my laboratory will use an innovative approach that combines state-of-the-art techniques including confocal microscopy and live animal imaging. These approaches will be used in conjunction with more traditional biochemical and immunological assays to assess the role of immune-receptors and adaptor proteins in iNKT cell killing. The successful completion of these studies will further our understanding of iNKT cell biology and help identify ways in which the cytotoxic function of these cells could be enhanced to augment host immunity to cancer.
- Sklarz T., Guan, P., Gohil, M., Cotton, R.M., Ge, M.Q., Haczku, A., Das, R., Jordan M.S. mTORC2 regulates multiple aspects of NKT-cell development and function. Eur J Immunol. 2017 Jan 12. doi: 10.1002/eji.201646343. [Epub ahead of print]
- Ruffo, E. *, Larens, S. *, Malacarne, V. *, Das, R. *, Patrussi, L., Schwartzberg, P., Wuelfing, C., Baldari, T. C., Rubio, I., Nichols, K.E., Snow, A., Graziani, A., Baldanzi, G. Inhibition of diacylglycerol kinase alpha rescues TCR-induced diacylglycerol signaling and restimulation induced cell death in XLP T lymphocytes. * Equal
contribution, share first authorship. Sci Transl Med. 2016 Jan; 8(321) 321 ra7
Web Link: http://stm.sciencemag.org/content/8/321/321ra7.short
- Guan, P., Bassiri, H., Patel, N.P., Nichols, K.E., Das, R. Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression. Bone Marrow Transplant. 2016 May; 51(5):629-37. doi: 10.1038/bmt.2015.335.
Web Link: http://www.nature.com/bmt/journal/v51/n5/full/bmt2015335a.html
- Das, R., Guan, P., Sprague, L., Teachey, D. T., Behrens, E.M., Wherry, J.E., Nichols, K.E. Janus kinase inhibition as a novel treatment for hemophagocytic lymphohistiocytosis. Blood. 2016 Mar 31;127(13):1666-75. doi: 10.1182/blood-2015-12-684399.
Web Link: http://www.bloodjournal.org/content/127/13/1666.
- Altman, J.B., Benavides, A.D., Das, R., Bassiri, H. Anti-tumor responses of invariant natural killer T cells. J Immunol Res. 2015; 2015:652875. doi: 10.1155/2015/652875
Web link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620262/
- Bassiri, H., Das, R., Nichols, K, E. Invariant Natural Killer T cells: Killers and conspirators against cancer. OncoImmunology. 2013 Dec 1;2(12):e27440.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/24575380
- Bassiri, H., Das, R., Guan, P., Barrett, D.M., Brennan, P.J., Banerjee, P.P., Wiener, S.J., Orange, J.S., Brenner, M.B., Grupp, S.A., Nichols, K.E. iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo. Cancer Immunol Res. 2014 Jan; 2(1): 59-69.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/24563871
- Chellapandian, D., Das, R., Zelly, K., Wiener, S. J., Zhao, H., Teachey, D.T., et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013 Aug; 162(3): 376-382. Web link: http://www.ncbi.nlm.nih.gov/pubmed/23692048
- Das, R., Bassiri, H., Guan, P., Wiener, S. J., Banerjee, P. P., Zhong, M., Veillette, A., Orange, J. S., Nichols, K.E. The adapter molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation. Blood. 2013 Apr 25; 121(17): 3386-3395.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/23430111
- Rothman, J.A. *, Das, R. *, Teachey, D.T., Paessler, M.E., Nichols, K.E. Rapamycin does not control hemophagocytic lymphohistiocytosis in LCMV-infected perforin-deficient mice. Pediatr Blood Cancer. 2011 Dec 15; 57(7): 1239-1243. * Equal contribution, share first authorship. Web link: http://www.ncbi.nlm.nih.gov/pubmed/21681935
- Rezaei, N., Mahmoudi, E., Aghamohammadi, A., Das, R., Nichols, K.E. X-Linked Lymphoproliferative Syndrome: A Genetic Condition Typified by the Triad of Epstein-Barr Virus Infection, Immunodeficiency and Lymphoma. Br J Haematol. 2011 Jan; 152(1): 13-30.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/21083659
- Das, R., Sant’Angelo, D.B., Nichols, K.E. Transcriptional control of invariant NKT cell development. Immunol Rev. 2010 Nov; 238(1): 195-215.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/20969594
- Das, R., Komorowski, R., Hessner, M., Subramanian, H., Huettner, C., Cua, D., Drobyski, W.R. Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft versus host and graft versus leukemia responses. Blood. 2010 Jun 24; 115(25): 5249-5258.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/20382845
- Chen, X., Das, R., Komorowski, R., van Snick, J., Uyttenhove, C., Drobyski,W.R. Interleukin 17 is not required for autoimmune-mediated pathological damage during chronic graft versus host disease. Biol Blood Marrow Transplant. 2010 Jan 16(1): 123-128. Web link: http://www.ncbi.nlm.nih.gov/pubmed/19772944
- Chen, X. *, Das, R. *, Komorowski, R., Beres, A., Hessner, M., Mihara, M., Drobyski,W.R. Blockade of interleukin 6 signaling augments regulatory T cell reconstitution and attenuates the severity of graft versus host disease. Blood. 2009 Jul 23; 114(4): 891-900. * Equal contribution, share first authorship.
Web link: http://www.ncbi.nlm.nih.gov/pubmed/19491393
- Das, R., Chen, X., Komorowski, R., Hessner, M., Drobyski,W.R. Interleukin-23 secretion by donor antigen presenting cells is critical for organ-specific pathology in graft versus host disease. Blood. 2009 Mar 5; 113(10): 2352-2362. Web link: http://www.ncbi.nlm.nih.gov/pubmed/19059877
- Das, R., Ponnappan, S., Ponnappan, U. Redox regulation of the proteasome in T lymphocytes during aging. Free Radic Biol Med. 2007 Feb 15; 42 (4): 541-551. Web link: http://www.ncbi.nlm.nih.gov/pubmed/17275686