Paulo <span>C.</span> Rodriguez, PhD
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Paulo C. Rodriguez, PhD

Academic Rank: Associate Member

Overview

The long-term goal of my research is to develop innovative strategies that restore protective immunity in cancer, leading to long lasting anti-tumor effector responses.

Discipline

    • Immunology
    • Malignant Hematology

Education & Training

    • CCBB-University of Antioquia, Masters - Immunology
    • Louisiana State University Health Sciences Center, PhD - Genetics
    • Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, Fellow - Immunotherapy
Research

Dr. Rodriguez's research programs focus on the suppressive effects induced by tumor-infiltrating myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid precursors that are primary mediators of tumor-induced anergy and a major obstacle for the development of successful cancer immunotherapies. My current research programs are summarized as following:1. To determine the role of major pathways associated with cellular stress in the tumor microenvironment as master regulators of the immune suppressive activity of MDSC. This research is based on the hypothesis that the activation of particular stress signals in MDSC drives their ability to inhibit T cell responses and modulates MDSC accumulation and survival in tumors. Therefore, therapeutic inhibition of these mediators and its major upstream regulators in tumors will reprogram MDSC function into functional anti-tumor antigen presenting cells, restore protective anti-tumor T cell responses, and increase the efficacy of various forms immunotherapy.2. To identify the importance of the inhibition of Notch1 signaling in CD8 T lymphocytes in the T cell anergy induced by MDSC in solid tumors. The Notch family of receptors mediates a highly conserved pathway that controls the function, development, and differentiation of many cell types, including immune cells. In this research project, we aim to elucidate the mechanisms whereby Notch1 activity in CD8 T cells counteracts MDSC-linked tolerance in tumors and to test the effect of triggering Notch1 signaling in T cells as a novel strategy to increase the efficacy of various forms of cancer immunotherapy. We are currently investigating several therapeutic approaches aimed at increasing Notch1 signaling in tumor-infiltrating CD8 T cells.3. To understand the role of the deprivation of the non-essential amino acid L-arginine in the suppressive function and accumulation of MDSC in tumors.  The metabolism of different amino acids, including L-Arginine, by tumor-infiltrating MDSC has been shown to impair anti-tumor T cell responses. Ongoing experiments are testing the effect of the deprivation of L-Arginine and other nutrients in the function and accumulation of MDSC in tumor-bearing hosts. This strategy is expected to enable the metabolic reprogramming of MDSC in tumors, thereby resulting in significant anti-tumor effects.

Publications

  • Al-Khami AA, Ghonim MA, Del Valle L, Ibba SV, Zheng L, Pyakurel K, Okpechi SC, Garay J, Wyczechowska D, Sanchez-Pino MD, Rodriguez PC, Boulares AH, Ochoa AC. Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target. Clin Exp Allergy. 2017 Sep;47(9):1170-1184. Pubmedid: 28456994. Pmcid: PMC5578913.
  • Islam BN, Sharman SK, Hou Y, Bridges AE, Singh N, Kim S, Kolhe R, Trillo-Tinoco J, Rodriguez PC, Berger FG, Sridhar S, Browning DD. Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice. Cancer Prev Res (Phila). 2017 Jul;10(7):377-388. Pubmedid: 28468928. Pmcid: PMC5530733.
  • Cubillos-Ruiz JR, Mohamed E, Rodriguez PC. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J Immunother Cancer. 2017 Jan;5:5. Pubmedid: 28105371. Pmcid: PMC5240216.
  • Rodriguez PC, Ochoa AC, Al-Khami AA. Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity. Front Immunol. 2017 Feb;8:93. Pubmedid: 28223985. Pmcid: PMC5293781.
  • Mohamed E, Cao Y, Rodriguez PC. Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol Immun. 2017 Aug;66(8):1069-1078. Pubmedid: 28577085.
  • Abu Eid R, Ahmad S, Lin Y, Webb M, Berrong Z, Shrimali R, Kumai T, Ananth S, Rodriguez PC, Celis E, Janik J, Mkrtichyan M, Khleif SN. Enhanced Therapeutic Efficacy and Memory of Tumor-Specific CD8 T Cells by Ex Vivo PI3K-δ Inhibition. Cancer Res. 2017 Aug;77(15):4135-4145. Pubmedid: 28615225.
  • Al-Khami AA, Rodriguez PC, Ochoa AC. Energy metabolic pathways control the fate and function of myeloid immune cells. J Leukoc Biol. 2017 Aug;102(2):369-380. Pubmedid: 28515225. Pmcid: PMC5505747.
  • Munn DH, Sharma MD, Johnson TS, Rodriguez P. IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunol Immun. 2017 Aug;66(8):1049-1058. Pubmedid: 28488123.
  • Kumai T, Celis E, Rodriguez PC. Editorial: A matter of survival: HMGB1 regulates autophagy in tumor MDSC. J Leukoc Biol. 2016 Sep;100(3):447-449. Pubmedid: 27587376.
  • Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016 Jul;7:12150. Pubmedid: 27381735. Pmcid: PMC4935811.
  • Al-Khami AA, Rodriguez PC, Ochoa AC. Metabolic reprogramming of myeloid-derived suppressor cells (MDSC) in cancer. Oncoimmunology. 2016 Aug;5(8):e1200771. Pubmedid: 27622069. Pmcid: PMC5007951.
  • Raber PL, Sierra RA, Thevenot PT, Shuzhong Z, Wyczechowska DD, Kumai T, Celis E, Rodriguez PC. T cells conditioned with MDSC show an increased anti-tumor activity after adoptive T cell based immunotherapy. Oncotarget. 2016 Apr;7(14):17565-17578. Pubmedid: 27007050. Pmcid: PMC4951233.
  • Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, Valle LD, Trillo-Tinoco J, Maj T, Zou W, Rodriguez PC, Ochoa AC. Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol Res. 2015 Nov;3(11):1236-1247. Pubmedid: 26025381. Pmcid: PMC4636942.
  • Ghonim MA, Pyakurel K, Ibba SV, Al-Khami AA, Wang J, Rodriguez P, Rady HF, El-Bahrawy AH, Lammi MR, Mansy MS, Al-Ghareeb K, Ramsay A, Ochoa A, Naura AS, Boulares AH. PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4(+) T cell function. J Transl Med. 2015 Jul;13:225. Pubmedid: 26169874. Pmcid: PMC4501284.
  • Fletcher M, Ramirez ME, Sierra RA, Raber P, Thevenot P, Al-Khami AA, Sanchez-Pino D, Hernandez C, Wyczechowska DD, Ochoa AC, Rodriguez PC. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015 Jan;75(2):275-283. Pubmedid: 25406192. Pmcid: PMC4297565.
  • Ghonim MA, Pyakurel K, Ju J, Rodriguez PC, Lammi MR, Davis C, Abughazleh MQ, Mansy MS, Naura AS, Boulares AH. DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4⁺ T-cell function without causing severe combined immunodeficiency. J Allergy Clin Immun. 2015 Feb;135(2):425-440. Pubmedid: 25441643. Pmcid: PMC4323872.
  • Ghonim MA, Pyakurel K, Ibba SV, Wang J, Rodriguez P, Al-Khami AA, Lammi MR, Kim H, Zea AH, Davis C, Okpechi S, Wyczechowska D, Al-Ghareeb K, Mansy MS, Ochoa A, Naura AS, Boulares AH. PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice. Clin Sci (Lond). 2015 Dec;129(11):951-962. Pubmedid: 26205779. Pmcid: PMC4613510.
  • Duque-Correa MA, Kühl AA, Rodriguez PC, Zedler U, Schommer-Leitner S, Rao M, Weiner J, Hurwitz R, Qualls JE, Kosmiadi GA, Murray PJ, Kaufmann SH, Reece ST. Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas. Proc Natl Acad Sci U S A. 2014 Sep;111(38):E4024-E4032. Pubmedid: 25201986. Pmcid: PMC4183271.
  • Dimitriades V, Rodriguez PC, Zabaleta J, Ochoa AC. Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis. Ann Allergy Asthma Immunol. 2014 Sep;113(3):271-275. Pubmedid: 25027824. Pmcid: PMC4517580.
  • Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P, Ochoa AC, Cui Y, Del Valle L, Rodriguez PC. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity. 2014 Sep;41(3):389-401. Pubmedid: 25238096. Pmcid: PMC4171711.
  • Raber PL, Thevenot P, Sierra R, Wyczechowska D, Halle D, Ramirez ME, Ochoa AC, Fletcher M, Velasco C, Wilk A, Reiss K, Rodriguez PC. Subpopulations of myeloid-derived suppressor cells impair T cell responses through independent nitric oxide-related pathways. Int J Cancer. 2014 Jun;134(12):2853-2864. Pubmedid: 24259296. Pmcid: PMC3980009.
  • Zhu X, Pribis JP, Rodriguez PC, Morris SM, Vodovotz Y, Billiar TR, Ochoa JB. The central role of arginine catabolism in T-cell dysfunction and increased susceptibility to infection after physical injury. Ann Surg. 2014 Jan;259(1):171-178. Pubmedid: 23470573.
  • Qin Z, Dai L, Trillo-Tinoco J, Senkal C, Wang W, Reske T, Bonstaff K, Del Valle L, Rodriguez P, Flemington E, Voelkel-Johnson C, Smith CD, Ogretmen B, Parsons C. Targeting sphingosine kinase induces apoptosis and tumor regression for KSHV-associated primary effusion lymphoma. Mol Cancer Ther. 2014 Jan;13(1):154-164. Pubmedid: 24140934. Pmcid: PMC3918494.
  • Sierra RA, Thevenot P, Raber PL, Cui Y, Parsons C, Ochoa AC, Trillo-Tinoco J, Del Valle L, Rodriguez PC. Rescue of notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol Res. 2014 Aug;2(8):800-811. Pubmedid: 24830414. Pmcid: PMC4125513.
  • Crittenden MR, Savage T, Cottam B, Baird J, Rodriguez PC, Newell P, Young K, Jackson AM, Gough MJ. Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice. Radiat Res. 2014 Aug;182(2):182-190. Pubmedid: 24992164.
  • Hill JM, Stern EM, Bhattacharjee PS, Malamud D, Clement C, Rodriguez P, Lukiw WJ, Ochoa AC, Foster TP, Velasco C, McFerrin HE. The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model. Antiviral Res. 2013 Oct;100(1):14-19. Pubmedid: 23860013. Pmcid: PMC3927842.
  • Wilk A, Waligórski P, Lassak A, Vashistha H, Lirette D, Tate D, Zea AH, Koochekpour S, Rodriguez P, Meggs LG, Estrada JJ, Ochoa A, Reiss K. Polycyclic aromatic hydrocarbons-induced ROS accumulation enhances mutagenic potential of T-antigen from human polyomavirus JC. J Cell Physiol. 2013 Nov;228(11):2127-2138. Pubmedid: 23558788. Pmcid: PMC4007759.
  • Guo G, Marrero L, Rodriguez P, Del Valle L, Ochoa A, Cui Y. Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res. 2013 Mar;73(6):1668-1675. Pubmedid: 23319800. Pmcid: PMC3602383.
  • Morrow K, Hernandez CP, Raber P, Del Valle L, Wilk AM, Majumdar S, Wyczechowska D, Reiss K, Rodriguez PC. Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia. Leukemia. 2013 Mar;27(3):569-577. Pubmedid: 22926702. Pmcid: PMC3594435.
  • Hernandez CP, Morrow K, Velasco C, Wyczechowska DD, Naura AS, Rodriguez PC. Effects of cigarette smoke extract on primary activated T cells. Cell Immunol. 2013 Mar;282(1):38-43. Pubmedid: 23665673. Pmcid: PMC3676722.
  • Naura AS, Kim H, Ju J, Rodriguez PC, Jordan J, Catling AD, Rezk BM, Abd Elmageed ZY, Pyakurel K, Tarhuni AF, Abughazleh MQ, Errami Y, Zerfaoui M, Ochoa AC, Boulares AH. Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor κB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase. J Biol Chem. 2013 Jan;288(3):1458-1468. Pubmedid: 23184953. Pmcid: PMC3548459.
  • Raber P, Ochoa AC, Rodríguez PC. Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest. 2012 Sep;41(6-7):614-634. Pubmedid: 23017138. Pmcid: PMC3519282.
  • Sarvaiya PJ, Schwartz JR, Hernandez CP, Rodriguez PC, Vedeckis WV. Role of c-Myb in the survival of pre B-cell acute lymphoblastic leukemia and leukemogenesis. Am J Hematol. 2012 Oct;87(10):969-976. Pubmedid: 22764095. Pmcid: PMC3578739.
  • Kibe R, Zhang S, Guo D, Marrero L, Tsien F, Rodriguez P, Khan S, Zieske A, Huang J, Li W, Durum SK, Iwakuma T, Cui Y. IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis. Cell Death Differ. 2012 Jul;19(7):1139-1151. Pubmedid: 22281704. Pmcid: PMC3374079.
  • Naura AS, Zerfaoui M, Kim H, Abd Elmageed ZY, Rodriguez PC, Hans CP, Ju J, Errami Y, Park J, Ochoa AC, Boulares AH. Requirement for inducible nitric oxide synthase in chronic allergen exposure-induced pulmonary fibrosis but not inflammation. J Immunol. 2010 Sep;185(5):3076-3085. Pubmedid: 20668217. Pmcid: PMC3077076.
  • Rodriguez PC, Hernandez CP, Morrow K, Sierra R, Zabaleta J, Wyczechowska DD, Ochoa AC. L-arginine deprivation regulates cyclin D3 mRNA stability in human T cells by controlling HuR expression. J Immunol. 2010 Nov;185(9):5198-5204. Pubmedid: 20889542. Pmcid: PMC3108892.
  • Hernandez CP, Morrow K, Lopez-Barcons LA, Zabaleta J, Sierra R, Velasco C, Cole J, Rodriguez PC. Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood. 2010 Jun;115(25):5214-5221. Pubmedid: 20407034. Pmcid: PMC2892956.
  • Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010 Jan;70(1):68-77. Pubmedid: 20028852. Pmcid: PMC2805057.
  • Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R, Taylor PA, Panoskaltsis-Mortari A, Serody JS, Munn DH, Tolar J, Ochoa AC, Blazar BR. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood. 2010 Dec;116(25):5738-5747. Pubmedid: 20807889. Pmcid: PMC3031417.
  • Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, Ochoa AC. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009 Feb;69(4):1553-1560. Pubmedid: 19201693. Pmcid: PMC2900845.
  • Norian LA, Rodriguez PC, O'Mara LA, Zabaleta J, Ochoa AC, Cella M, Allen PM. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. 2009 Apr;69(7):3086-3094. Pubmedid: 19293186. Pmcid: PMC2848068.
  • Zheng L, Asprodites N, Keene AH, Rodriguez P, Brown KD, Davila E. TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements. Blood. 2008 Mar;111(5):2704-2713. Pubmedid: 18086870. Pmcid: PMC2254540.
  • Rodríguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008 Apr;222:180-191. Pubmedid: 18364002. Pmcid: PMC3546504.
  • Ochoa AC, Zea AH, Hernandez C, Rodriguez PC. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res. 2007 Jan;13(2 Pt 2):721s-726s. Pubmedid: 17255300.
  • Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 2007 Feb;109(4):1568-1573. Pubmedid: 17023580. Pmcid: PMC1794048.
  • Rodríguez PC, Ochoa AC. T cell dysfunction in cancer: role of myeloid cells and tumor cells regulating amino acid availability and oxidative stress. Semin Cancer Biol. 2006 Feb;16(1):66-72. Pubmedid: 16298138.
  • Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 2006 Apr;203(4):871-881. Pubmedid: 16606666. Pmcid: PMC2118300.
  • Di Costanzo L, Sabio G, Mora A, Rodriguez PC, Ochoa AC, Centeno F, Christianson DW. Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response. Proc Natl Acad Sci U S A. 2005 Sep;102(37):13058-13063. Pubmedid: 16141327. Pmcid: PMC1201588.
  • Campoli M, Ferrone S, Zea AH, Rodriguez PC, Ochoa AC. Mechanisms of tumor evasion. Cancer Treat Res. 2005 Oct;123:61-88. Pubmedid: 16211866.
  • Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med. 2005 Oct;202(7):931-939. Pubmedid: 16186186. Pmcid: PMC2213169.
  • Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O'Neill A, Mier J, Ochoa AC. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005 Apr;65(8):3044-3048. Pubmedid: 15833831.
  • Zea AH, Rodriguez PC, Culotta KS, Hernandez CP, DeSalvo J, Ochoa JB, Park HJ, Zabaleta J, Ochoa AC. L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cell Immunol. 2004 Nov;232(1-2):21-31. Pubmedid: 15922712.
  • Bansal V, Rodriguez P, Wu G, Eichler DC, Zabaleta J, Taheri F, Ochoa JB. Citrulline can preserve proliferation and prevent the loss of CD3 zeta chain under conditions of low arginine. JPEN J Parenter Enteral Nutr. 2004 Nov;28(6):423-430. Pubmedid: 15568289.
  • Zabaleta J, McGee DJ, Zea AH, Hernández CP, Rodriguez PC, Sierra RA, Correa P, Ochoa AC. Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta). J Immunol. 2004 Jul;173(1):586-593. Pubmedid: 15210820.
  • Rodriguez P, Quiceno D, Zabaleta J, Ortiz B, Zea A, Piazuelo M, Delgado A, Correa P, Brayer J, Sotomayor E, Antonia S, Ochoa J, Ochoa A. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004 Aug;64(16):5839-5849. Pubmedid: 15313928.
  • Rodríguez PC, Zea AH, Ochoa AC. Mechanisms of tumor evasion from the immune response. Cancer Chemother Biol Response Modif. 2003 Feb;21:351-364. Pubmedid: 15338755.
  • Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, Ochoa JB, Ochoa AC. L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol. 2003 Aug;171(3):1232-1239. Pubmedid: 12874210.
  • Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem. 2002 Jun;277(24):21123-21129. Pubmedid: 11950832.
  • Rodríguez PC, Arroyave IH, Mejía G, García LF. Detection of alloantibodies against non-HLA antigens in kidney transplantation by flow cytometry. Clin Transplant. 2000 Oct;14(5):472-478. Pubmedid: 11048992.
  • Rodríguez PC, Palacio JL, Arango L, Henao JE, García LF. Detection of allo- and autoantibodies in kidney transplantation by flow cytometry. Transplant P. 1999 Feb;31(1-2):282-284. Pubmedid: 10083109.