Department of Microbiology and Immunology
Chrystal Paulos, PhD
2004-2007 Postdoctoral Fellow, Surgery Branch, NCI, NIH
2007-2011 Postdoctoral Fellow, University of Pennsylvania
Our laboratory focuses on developing novel T-cell immunotherapies for patients with advanced cancer. Our strategy is based on the use of mouse models to develop human clinical trials that effectively harness the patient’s own immune system to kill cancer.
We study new ways to improve adoptive cell transfer (ACT) therapy, which involves removal of T cells from the patient, their expansion/manipulation ex-vivo, followed by their return to patient preconditioned with lymphodepletion via chemotherapy agents and/or total body irradiation.
Lymphodepletion significantly enhances the efficacy of ACT therapies. However, host conditioning with lymphodepletion is not the only factor that positively impacts clinical outcome. We and other investigators have found that the functional properties of T cells are critical for successful tumor immunotherapy.
We have very recently found that CD4 and CD8 T cells that produce IL-17 (Th17 and Tc17 cells, respectively) mediate robust tumor regression. Additional investigation revealed that the expansion of Th17/Tc17 cells with the costimulatory molecule ICOS but not CD28 further improved their function and their ability to eradiate large tumors (see Fig1). Although ICOS-expanded Th17/Tc17 cells mediate potent tumor regression, the cellular, biochemical and molecular mechanisms underlying how ICOS signaling drives the differentiation and expansion of cells that produce high levels of IL-17, IL-21 and IFN-gamma compared to those stimulated with CD28 remains incompletely elucidated. Thus, we are now investigating key transcription factors regulated by ICOS versus CD28 that distinctly impact their functional fate. We are also investigating the mechanism governing the in vivo effectiveness of ICOS-expanded tumor-specific Tc17/Th17 cells using the clinically relevant transgenic ACT mouse models of cancer created in Dr. Nicholas Restifo’s laboratory.
In summary, research in the Paulos laboratory will focus on broadening the utility and efficacy of the ACT approach. We are particularly interested in improving host preconditioning regimens as well as augmenting various T-cell subsets by ex-vivo and in-vivo manipulation with novel cytokine/chemical cocktails and with ICOS agonists (as well as with other costimulatory molecules). We believe that our investigations will provide vital information on how to build on the next generation of T-cell based immunotherapies for cancer as well as for autoimmunity and infectious diseases.
Recent Publications | Additional Publications
Enhanced lymphodepletion is insufficient to replace exogenous IL-2 or IL-15 therapy in augmenting the efficacy of adoptively transferred effector CD8+ T cells.
Johnson CB, May BR, Riesenberg BP, Suriano S, Mehrotra S, Garret-Mayer E, Salem ML, Jeng EK, Wong HC, Paulos CM, Wrangle J, Cole DJ, Rubinstein MP.
Cancer Res. 2018 Apr 10. pii: canres.2153.2017. doi: 10.1158/0008-5472.CAN-17-2153. [Epub ahead of print]
When worlds collide: Th17 and Treg cells in cancer and autoimmunity.
Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, Paulos CM.
Cell Mol Immunol. 2018 Mar 21. doi: 10.1038/s41423-018-0004-4. [Epub ahead of print] Review.
IL-2 and Beyond in Cancer Immunotherapy.
Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, Paulos CM, Li Z, Cole DJ, Rubinstein MP.
J Interferon Cytokine Res. 2018 Feb;38(2):45-68. doi: 10.1089/jir.2017.0101.
N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner.
Scheffel MJ, Scurti G, Wyatt MM, Garrett-Mayer E, Paulos CM, Nishimura MI, Voelkel-Johnson C.
Cancer Immunol Immunother. 2018 Apr;67(4):691-702. doi: 10.1007/s00262-018-2120-5. Epub 2018 Feb 2.
The clinical implications of immunogenomics in colorectal cancer: A path for precision medicine.
Riley JM, Cross AW, Paulos CM, Rubinstein MP, Wrangle J, Camp ER.
Cancer. 2018 Apr 15;124(8):1650-1659. doi: 10.1002/cncr.31214. Epub 2018 Jan 9. Review.
Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence.
Bailey SR, Nelson MH, Majchrzak K, Bowers JS, Wyatt MM, Smith AS, Neal LR, Shirai K, Carpenito C, June CH, Zilliox MJ, Paulos CM.
Nat Commun. 2017 Dec 6;8(1):1961. doi: 10.1038/s41467-017-01867-9.
Adoptive Transfer of Ceramide Synthase 6 Deficient Splenocytes Reduces the Development of Colitis.
Scheffel MJ, Helke K, Lu P, Bowers JS, Ogretmen B, Garrett-Mayer E, Paulos CM, Voelkel-Johnson C.
Sci Rep. 2017 Nov 14;7(1):15552. doi: 10.1038/s41598-017-15791-x.
CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.
Chatterjee S, Daenthanasanmak A, Chakraborty P, Wyatt MW, Dhar P, Selvam SP, Fu J, Zhang J, Nguyen H, Kang I, Toth K, Al-Homrani M, Husain M, Beeson G, Ball L, Helke K, Husain S, Garrett-Mayer E, Hardiman G, Mehrotra M, Nishimura MI, Beeson CC, Bupp MG, Wu J, Ogretmen B, Paulos CM, Rathmell J, Yu XZ, Mehrotra S.
Cell Metab. 2018 Jan 9;27(1):85-100.e8. doi: 10.1016/j.cmet.2017.10.006. Epub 2017 Nov 9.
PI3Kδ Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells.
Bowers JS, Majchrzak K, Nelson MH, Aksoy BA, Wyatt MM, Smith AS, Bailey SR, Neal LR, Hammerbacher JE, Paulos CM.
Front Immunol. 2017 Sep 29;8:1221. doi: 10.3389/fimmu.2017.01221. eCollection 2017.
Inducible Enhancement of T Cell Function and Anti-tumor Activity after Adoptive Transfer.
Wrangle J, Paulos CM, Smith TW Jr., Nishimura MI, Rubinstein MP.
Mol Ther. 2017 Sep 6;25(9):1995-1996. doi: 10.1016/j.ymthe.2017.08.002. Epub 2017 Aug 19. No abstract available.