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Chrystal M Paulos, PhD
Assistant Professor of Microbiology & Immunology
College of Medicine
MUSC

Email: paulos@musc.edu
 
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Chrystal M Paulos, PhD

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Research Interest:

Our laboratory investigates the potential role of human IL-17 producing cells in tumor immunity. To address this question, we polarized tumor-specific human T cells toward a Type 17 phenotype using cytokines IL-1 beta, IL-6 and IL-23 and expanded them using anti-CD3/28 beads. However, we found that the in vitro functionality of these cells decreased within two weeks, as indicated by their reduced capacity to produce IL-17. Unexpectedly, this loss in function was found to be a consequence of CD28 signaling. These data indicated that cytokines were not the only factors that regulate human Th17 differentiation, and that costimulatory molecules might also be critically important in shaping their fate. We found that ICOS costimulation specifically promotes the outgrowth and augments the function of peripheral and cord blood Th17 cells with an effector memory phenotype. This phenotype was maintained in long-term culture. Thus, CD28 and ICOS costimulation have non-redundant roles in the generation of inflammatory human Type17 cells. Of significant clinical importance, adoptive transfer of ICOS-expanded human Type 17 cells into NOD/Scid/IL-2r?c-/- mice mediated superior eradication of large human mesotheliomas, compared with adoptive transfer of CD28-expanded Type 17 cells or other T cells subsets. We are now investigating how ICOS signaling modulates key transcription factors that impact the function fate of inflammatory Th17/Tc17 cells and the mechanisms governing the effectiveness of ICOS-expanded Th17/Tc17 cells using a highly clinically relevant cancer mouse model. These findings revealed that ICOS-expanded human IL-17 producing cells enhance immunity to tumor antigens, which have profound implications for cancer immunotherapy.

Selected Publications:

1.Andrijauskaite K, Suriano S, Cloud CA, Li M, Kesarwani P, Stefanik LS, Moxley KM, Salem ML, Garrett-Mayer E, Paulos CM, Mehrotra S, Kochenderfer JN, Cole DJ, Rubinstein MP. IL-12 conditioning improves retrovirally mediated transduction efficiency of CD8(+) T cells. Cancer Gene Ther. .22(7):360-7, 2015.
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2.Nelson MH, Diven MA, Huff LW, Paulos CM. Harnessing the Microbiome to Enhance Cancer Immunotherapy. J Immunol Res. .2015:368736, 2015. PMCID: PMC4458560
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3.Bowers JS, Nelson MH, Kundimi S, Bailey SR, Huff LW, Schwartz KM, Cole DJ, Rubinstein MP, Paulos CM. Dendritic Cells in Irradiated Mice Trigger the Functional Plasticity and Antitumor Activity of Adoptively Transferred Tc17 Cells via IL12 Signaling. Clin Cancer Res. .21(11):2546-57, 2015. PMCID: PMC4452402
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4.Rubinstein MP, Su EW, Suriano S, Cloud CA, Andrijauskaite K, Kesarwani P, Schwartz KM, Williams KM, Johnson CB, Li M, Scurti GM, Salem ML, Paulos CM, Garrett-Mayer E, Mehrotra S, Cole DJ. Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells. Cancer Immunol Immunother. .64(5):539-49, 2015.
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5.Frigault MJ, Lee J, Basil MC, Carpenito C, Motohashi S, Scholler J, Kawalekar OU, Guedan S, McGettigan SE, Posey AD, Ang S, Cooper LJ, Platt JM, Johnson FB, Paulos CM, Zhao Y, Kalos M, Milone MC, June CH. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol Res. .3(4):356-67, 2015. PMCID: PMC4390458
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6.Nelson MH, Kundimi S, Bowers JS, Rogers CE, Huff LW, Schwartz KM, Thyagarajan K, Little EC, Mehrotra S, Cole DJ, Rubinstein MP, Paulos CM. The inducible costimulator augments Tc17 cell responses to self and tumor tissue. J Immunol. .194(4):1737-47, 2015. PMCID: PMC4323681
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7.Nelson MH, Paulos CM. Novel immunotherapies for hematologic malignancies. Immunol Rev. .263(1):90-105, 2015. PMCID: PMC4277117
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8.Chatterjee S, Thyagarajan K, Kesarwani P, Song JH, Soloshchenko M, Fu J, Bailey SR, Vasu C, Kraft AS, Paulos CM, Yu XZ, Mehrotra S. Reducing CD73 expression by IL1ß-Programmed Th17 cells improves immunotherapeutic control of tumors. Cancer Res. .74(21):6048-59, 2014. PMCID: PMC4216762
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9.Bailey SR, Nelson MH, Himes RA, Li Z, Mehrotra S, Paulos CM. Th17 cells in cancer: the ultimate identity crisis. Front Immunol. .5:276, 2014. PMCID: PMC4060300
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10.Rubinstein MP, Cloud CA, Garrett TE, Moore CJ, Schwartz KM, Johnson CB, Craig DH, Salem ML, Paulos CM, Cole DJ. Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg. .214(4):700-7; discussion 707-8, 2012. PMCID: PMC3429131
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11.Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, Wang E, Douek DC, Price DA, June CH, Marincola FM, Roederer M, Restifo NP. A human memory T cell subset with stem cell-like properties. Nat Med. .17(10):1290-7, 2011. PMCID: PMC3192229
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12.Zhang Q, Wang H, Kantekure K, Paterson JC, Liu X, Schaffer A, Paulos C, Milone MC, Odum N, Turner S, Marafioti T, Wasik MA. Oncogenic tyrosine kinase NPM-ALK induces expression of the growth-promoting receptor ICOS. Blood. .118(11):3062-71, 2011. PMCID: PMC3175783
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13.Paulos CM, Carpenito C, Plesa G, Suhoski MM, Varela-Rohena A, Golovina TN, Carroll RG, Riley JL, June CH. The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Sci Transl Med. .2(55):55ra78, 2010.
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14.Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL, Albelda SM, June CH. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. .70(22):9053-61, 2010. PMCID: PMC2982929
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15.Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. .33(1):1-7, 2010. PMCID: PMC3247626
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16.Paulos CM, June CH. Putting the brakes on BTLA in T cell-mediated cancer immunotherapy. J Clin Invest. .120(1):76-80, 2009. PMCID: PMC2798708
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17.Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. .15(7):808-13, 2009. PMCID: PMC2707501
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18.Hinrichs CS, Kaiser A, Paulos CM, Cassard L, Sanchez-Perez L, Heemskerk B, Wrzesinski C, Borman ZA, Muranski P, Restifo NP. Type 17 CD8+ T cells display enhanced antitumor immunity. Blood. .114(3):596-9, 2009. PMCID: PMC2713473
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19.Boni A, Muranski P, Cassard L, Wrzesinski C, Paulos CM, Palmer DC, Gattinoni L, Hinrichs CS, Chan CC, Rosenberg SA, Restifo NP. Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers. Blood. .112(12):4746-54, 2008. PMCID: PMC2597140
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20.Palmer DC, Chan CC, Gattinoni L, Wrzesinski C, Paulos CM, Hinrichs CS, Powell DJ, Klebanoff CA, Finkelstein SE, Fariss RN, Yu Z, Nussenblatt RB, Rosenberg SA, Restifo NP. Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci U S A. .105(23):8061-6, 2008. PMCID: PMC2409137
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21.Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, Paulos CM, Palmer DC, Touloukian CE, Ptak K, Gattinoni L, Wrzesinski C, Hinrichs CS, Kerstann KW, Feigenbaum L, Chan CC, Restifo NP. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. .112(2):362-73, 2008. PMCID: PMC2442746
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22.Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW, Palmer DC, Klebanoff CA, Rosenberg SA, Leonard WJ, Restifo NP. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood. .111(11):5326-33, 2008. PMCID: PMC2396726
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23.Abad JD, Wrzensinski C, Overwijk W, De Witte MA, Jorritsma A, Hsu C, Gattinoni L, Cohen CJ, Paulos CM, Palmer DC, Haanen JB, Schumacher TN, Rosenberg SA, Restifo NP, Morgan RA. T-cell receptor gene therapy of established tumors in a murine melanoma model. J Immunother. .31(1):1-6, 2008. PMCID: PMC2235937
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24.Paulos CM, Suhoski MM, Plesa G, Jiang T, Basu S, Golovina TN, Jiang S, Aqui NA, Powell DJ, Levine BL, Carroll RG, Riley JL, June CH. Adoptive immunotherapy: good habits instilled at youth have long-term benefits. Immunol Res. .42(1-3):182-96, 2008. PMCID: PMC3809041
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25.Paulos CM, Kaiser A, Wrzesinski C, Hinrichs CS, Cassard L, Boni A, Muranski P, Sanchez-Perez L, Palmer DC, Yu Z, Antony PA, Gattinoni L, Rosenberg SA, Restifo NP. Toll-like receptors in tumor immunotherapy. Clin Cancer Res. .13(18 Pt 1):5280-9, 2007. PMCID: PMC2131730
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26.Paulos CM, Wrzesinski C, Kaiser A, Hinrichs CS, Chieppa M, Cassard L, Palmer DC, Boni A, Muranski P, Yu Z, Gattinoni L, Antony PA, Rosenberg SA, Restifo NP. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest. .117(8):2197-204, 2007. PMCID: PMC1924500
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27.Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, Rosenberg SA, Restifo NP. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. .117(2):492-501, 2007. PMCID: PMC1783812
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28.Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, Heinrichs C, Klebanoff CA, Tagaya Y, Restifo NP. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol. .176(9):5255-66, 2006. PMCID: PMC1473163
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29.Paulos CM, Varghese B, Widmer WR, Breur GJ, Vlashi E, Low PS. Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis. Arthritis Res Ther. .8(3):R77, 2006. PMCID: PMC1526647
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30.Paulos CM, Reddy JA, Leamon CP, Turk MJ, Low PS. Ligand binding and kinetics of folate receptor recycling in vivo: impact on receptor-mediated drug delivery. Mol Pharmacol. .66(6):1406-14, 2004.
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31.Paulos CM, Turk MJ, Breur GJ, Low PS. Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. Adv Drug Deliv Rev. .56(8):1205-17, 2004.
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32.Turk MJ, Breur GJ, Widmer WR, Paulos CM, Xu LC, Grote LA, Low PS. Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. Arthritis Rheum. .46(7):1947-55, 2002.
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