Photo of Rachael A. Clark,  MD, PhD

Rachael A. Clark, MD, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-8512
Fax: (617) 264-5123


rclark1@partners.org

Rachael A. Clark, MD, PhD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Dermatology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our research focuses on the study of human T cell responses in skin and other peripheral tissues, including T cell function in healthy skin, impaired T cell migration and responses in skin cancers, and maladaptive T cell activation in inflammatory skin diseases and cutaneous lymphomas. We found that healthy adult human skin contains approximately 20 billion memory T cells, twice as many as are present in the circulation, leading to the discovery of resident memory T cells in skin. Nonrecirculating resident memory T cells play critical roles in defending skin against infection, but aberrant activation of these can lead to inflammatory diseases such as psoriasis and malignant transformation can give rise to cutaneous lymphomas . Skin cancers, including squamous cell carcinoma, melanoma and Merkel cell carcinoma, have evolved mechanisms for excluding or silencing resident memory T cells. Our studies, driven by observations in patients and carried out on human tissues, have the goals of developing novel therapies for skin disease and advancing our understanding of human immune responses.

Publications from Harvard Catalyst Profiles

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  • Weiner DM, Lewis DJ, Spaccarelli NG, Clark RA, Nasta SD, Loren AW, Rook AH, Kim EJ. Management of Relapsed Cutaneous T-Cell Lymphoma Following Allogeneic Hematopoietic Stem Cell Transplantation: Review with Representative Patient Case. Dermatol Ther 2022. PubMed
  • Matos TR, Gehad A, Teague JE, Dyring-Andersen B, Benezeder T, Dowlatshahi M, Crouch J, Watanabe Y, O'Malley JT, Kupper TS, Yang C, Watanabe R, Clark RA. Central memory T cells are the most effective precursors of resident memory T cells in human skin. Sci Immunol 2022; 7:eabn1889. PubMed
  • van Santen S, Zoutman WH, de Masson A, Quint KD, Willemze R, Gerard N, Teague JE, Kupper TS, Clark RA, Tensen CP, Vermeer MH. Tumor clone frequency calculation using high throughput sequencing of the T-cell receptor β gene in folliculotropic mycosis fungoides patients. J Invest Dermatol 2022. PubMed
  • Giustiniani J, Dobos G, Moins-Teisserenc H, Eustaquio T, Battistella M, Ortonne N, Ram-Wolff C, Bouaziz JD, Marie-Cardine A, Mourah S, Bagot M, Kupper T, Clark RA, Bensussan A, de Masson A. CCR8 is a new therapeutic target in cutaneous T-cell lymphomas. Blood Adv 2022. PubMed
  • Yu KK, Smith NP, Essien SV, Teague JE, Vieyra-Garcia P, Gehad A, Zhan Q, Crouch JD, Gerard N, Larocca C, Wolf P, LeBoeuf NR, Tawa M, Kupper TS, Villani AC, Clark RA. IL-32 supports the survival of malignant T cells in cutaneous T cell lymphoma. J Invest Dermatol 2022. PubMed
  • Cotton RN, Wegrecki M, Cheng TY, Chen YL, Veerapen N, Le Nours J, Orgill DP, Pomahac B, Talbot SG, Willis R, Altman JD, de Jong A, Van Rhijn I, Clark RA, Besra GS, Ogg G, Rossjohn J, Moody DB. CD1a selectively captures endogenous cellular lipids that broadly block T cell response. J Exp Med 2021. PubMed
  • Vieyra-Garcia PA, Cerroni L, Clark RA, Wolf P. Lupus erythematosus tumidus in a patient with mycosis fungoides stage IB after complete response to PUVA. 2021. PubMed
  • Cotton RN, Cheng TY, Wegrecki M, Le Nours J, Orgill DP, Pomahac B, Talbot SG, Willis RA, Altman JD, de Jong A, Ogg G, Van Rhijn I, Rossjohn J, Clark RA, Moody DB. Human skin is colonized by T cells that recognize CD1a independently of lipid. J Clin Invest 2021. PubMed
  • Durgin JS, Jariwala NN, Wysocka M, Zhang KK, Maity A, Benoit B, Plastaras JP, Lewis DJ, Rosenthal JM, Teague JE, Berg S, Del Guzzo C, Kim EJ, Vittorio C, Haun PL, Samimi SS, Villasenor-Park J, Inverso J, Clark RA, Rook AH. Low-Dose Total Skin Electron Beam Therapy as Part of a Multimodality Regimen for Treatment of Sézary Syndrome: Clinical, Immunologic, and Molecular Analysis. JAMA Dermatol 2021; 157:90-95. PubMed
  • Divito SJ, Aasebo AT, Matos TR, Hsieh PC, Collin M, Elco CP, O'Malley JT, Bækkevold ES, Reims HM, Gedde-Dahl T, Hagerstrom M, Hilaire J, Lian JW, Milford EL, Pinkus GS, Ho VT, Soiffer RJ, Kim HT, Mihm MC, Ritz J, Guleria I, Cutler CS, Clark R, Jahnsen FL, Kupper TS. Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host-disease. J Clin Invest 2020. PubMed
  • Pruessmann W, Rytlewski J, Wilmott J, Mihm MC, Attrill GH, Dyring-Andersen B, Fields P, Zhan Q, Colebatch AJ, Ferguson PM, Thompson JF, Kallenbach K, Yusko E, Clark RA, Robins H, Scolyer RA, Kupper TS. Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence. 2020; 1:197-209. PubMed
  • Dyring-Andersen B, Løvendorf MB, Coscia F, Santos A, Møller LBP, Colaço AR, Niu L, Bzorek M, Doll S, Andersen JL, Clark RA, Skov L, Teunissen MBM, Mann M. Spatially and cell-type resolved quantitative proteomic atlas of healthy human skin. Nat Commun 2020; 11:5587. PubMed
  • Blümel E, Munir Ahmad S, Nastasi C, Willerslev-Olsen A, Gluud M, Fredholm S, Hu T, Surewaard BGJ, Lindahl LM, Fogh H, Koralov SB, Rahbek Gjerdrum LM, Clark RA, Iversen L, Krejsgaard T, Bonefeld CM, Geisler C, Becker JC, Woetmann A, Andersen MH, Buus TB, Ødum N. alpha-toxin inhibits CD8 T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma. Oncoimmunology 2020; 9:1751561. PubMed
  • O'Malley JT, de Masson A, Lowry EL, Giobbie-Hurder A, LeBoeuf NR, Larocca C, Gehad A, Seger E, Teague JE, Fisher DC, Kupper TS, Devlin PM, Clark RA. Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides. Clin Cancer Res 2019. PubMed
  • Vieyra-Garcia P, Crouch JD, O'Malley JT, Seger EW, Yang CH, Teague JE, Vromans AM, Gehad A, Win TS, Yu Z, Lowry EL, Na JI, Rook AH, Wolf P, Clark RA. Benign T cells drive clinical skin inflammation in cutaneous T cell lymphoma. JCI Insight 2019. PubMed
  • Clark RA. Harnessing TORC to boost the horsepower of aging immune systems. Sci Immunol 2018. PubMed
  • de Masson A, O'Malley JT, Elco CP, Garcia SS, Divito SJ, Lowry EL, Tawa M, Fisher DC, Devlin PM, Teague JE, Leboeuf NR, Kirsch IR, Robins H, Clark RA, Kupper TS. High-throughput sequencing of the T cell receptor β gene identifies aggressive early-stage mycosis fungoides. Sci Transl Med 2018. PubMed
  • Clark RA. Resident memory T cells: Runx and hide. Sci Immunol 2018. PubMed
  • Jain S, Washington A, Leaf RK, Bhargava P, Clark RA, Kupper TS, Stroopinsky D, Pyzer A, Cole L, Nahas M, Apel A, Rosenblatt J, Arnason J, Kufe D, Avigan D. Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma. Mol Cancer Ther 2017; 16:2304-2314. PubMed
  • Pan Y, Tian T, Park CO, Lofftus SY, Mei S, Liu X, Luo C, O'Malley JT, Gehad A, Teague JE, Divito SJ, Fuhlbrigge R, Puigserver P, Krueger JG, Hotamisligil GS, Clark RA, Kupper TS. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 2017; 543:252-256. PubMed
  • Mauldin IS, Wages NA, Stowman AM, Wang E, Olson WC, Deacon DH, Smith KT, Galeassi N, Teague JE, Smolkin ME, Chianese-Bullock KA, Clark RA, Petroni GR, Marincola FM, Mullins DW, Slingluff CL. Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. Cancer Immunol Immunother 2016; 65:1201-12. PubMed
  • Clark SL, Tse JY, Fisher DC, LeBeouf NR, Murphy GF, Kupper TS, Clark RA, Lian CG. Histopathologic spectrum of hypersensitivity reactions associated with anti-CD52 therapy (alemtuzumab). J Cutan Pathol 2016. PubMed
  • Townsend EC, Murakami MA, Christodoulou A, Christie AL, Köster J, DeSouza TA, Morgan EA, Kallgren SP, Liu H, Wu SC, Plana O, Montero J, Stevenson KE, Rao P, Vadhi R, Andreeff M, Armand P, Ballen KK, Barzaghi-Rinaudo P, Cahill S, Clark RA, Cooke VG, Davids MS, DeAngelo DJ, Dorfman DM, Eaton H, Ebert BL, Etchin J, Firestone B, Fisher DC, Freedman AS, Galinsky IA, Gao H, Garcia JS, Garnache-Ottou F, Graubert TA, Gutierrez A, Halilovic E, Harris MH, Herbert ZT, Horwitz SM, Inghirami G, Intlekoffer AM, Ito M, Izraeli S, Jacobsen ED, Jacobson CA, Jeay S, Jeremias I, Kelliher MA, Koch R, Konopleva M, Kopp N, Kornblau SM, Kung AL, Kupper TS, LaBoeuf N, LaCasce AS, Lees E, Li LS, Look AT, Murakami M, Muschen M, Neuberg D, Ng SY, Odejide OO, Orkin SH, Paquette RR, Place AE, Roderick JE, Ryan JA, Sallan SE, Shoji B, Silverman LB, Soiffer RJ, Steensma DP, Stegmaier K, Stone RM, Tamburini J, Thorner AR, van Hummelen P, Wadleigh M, Wiesmann M, Weng AP, Wuerthner JU, Williams DA, Wollison BM, Lane AA, Letai A, Bertagnolli MM, Ritz J, Brown M, Long H, Aster JC, Shipp MA, Griffin JD, Weinstock DM. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 2016; 29:574-86. PubMed
  • Kirsch IR, Watanabe R, O'Malley JT, Williamson DW, Scott LL, Elco CP, Teague JE, Gehad A, Lowry EL, LeBoeuf NR, Krueger JG, Robins HS, Kupper TS, Clark RA. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med 2015; 7:308ra158. PubMed
  • Rook AH, Gelfand JC, Wysocka M, Troxel AB, Benoit B, Surber C, Elenitsas R, Buchanan MA, Leahy DS, Watanabe R, Kirsch IR, Kim EJ, Clark RA. Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood 2015; 126:1452-61. PubMed
  • Jain S, Stroopinsky D, Yin L, Rosenblatt J, Alam M, Bhargava P, Clark RA, Kupper TS, Palmer K, Coll MD, Rajabi H, Pyzer A, Bar-Natan M, Luptakova K, Arnason J, Joyce R, Kufe D, Avigan D. Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma. Blood 2015; 126:354-62. PubMed
  • Watanabe R, Gehad A, Yang C, Scott LL, Teague JE, Schlapbach C, Elco CP, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med 2015; 7:279ra39. PubMed
  • Guenova E, Skabytska Y, Hoetzenecker W, Weindl G, Sauer K, Tham M, Kim KW, Park JH, Seo JH, Ignatova D, Cozzio A, Levesque MP, Volz T, Köberle M, Kaesler S, Thomas P, Mailhammer R, Ghoreschi K, Schäkel K, Amarov B, Eichner M, Schaller M, Clark RA, Röcken M, Biedermann T. IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci U S A 2015; 112:2163-8. PubMed
  • Watanabe R, Teague JE, Fisher DC, Kupper TS, Clark RA. Alemtuzumab therapy for leukemic cutaneous T-cell lymphoma: diffuse erythema as a positive predictor of complete remission. JAMA Dermatol 2014. PubMed
  • Maldonado L, Teague JE, Morrow MP, Jotova I, Wu TC, Wang C, Desmarais C, Boyer JD, Tycko B, Robins HS, Clark RA, Trimble CL. Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. Sci Transl Med 2014; 6:221ra13. PubMed
  • Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE, Campbell L, Yawalkar N, Kupper TS, Clark RA. Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med 2014; 6:219ra8. PubMed
  • Guenova E, Watanabe R, Teague JE, Desimone JA, Jiang Y, Dowlatshahi M, Schlapbach C, Schaekel K, Rook AH, Tawa M, Fisher DC, Kupper TS, Clark RA. TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin Cancer Res 2013; 19:3755-63. PubMed
  • Dowlatshahi M, Huang V, Gehad AE, Jiang Y, Calarese A, Teague JE, Dorosario AA, Cheng J, Nghiem P, Schanbacher CF, Thakuria M, Schmults CD, Wang LC, Clark RA. Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses. J Invest Dermatol 2013. PubMed
  • Gehad AE, Lichtman MK, Schmults CD, Teague JE, Calarese AW, Jiang Y, Watanabe R, Clark RA. Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E-selectin expression in human squamous cell carcinomas. J Invest Dermatol 2012; 132:2642-51. PubMed
  • Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 2012. PubMed
  • Clark RA, Shackelton JB, Watanabe R, Calarese A, Yamanaka K, Campbell JJ, Teague JE, Kuo HP, Hijnen D, Kupper TS. High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma. Blood 2011; 117:1966-76. PubMed
  • de Jong A, Peña-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB. CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire. Nat Immunol 2010; 11:1102-9. PubMed
  • Trimble CL, Clark RA, Thoburn C, Hanson NC, Tassello J, Frosina D, Kos F, Teague J, Jiang Y, Barat NC, Jungbluth AA. Human papillomavirus 16-associated cervical intraepithelial neoplasia in humans excludes CD8 T cells from dysplastic epithelium. J Immunol 2010; 185:7107-14. PubMed
  • Cedeno-Laurent F, Barthel SR, Opperman MJ, Lee DM, Clark RA, Dimitroff CJ. Development of a nascent galectin-1 chimeric molecule for studying the role of leukocyte galectin-1 ligands and immune disease modulation. J Immunol 2010; 185:4659-72. PubMed
  • Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and MF arise from distinct T cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 2010; 116:767-71. PubMed
  • van Geel NA, Mollet IG, De Schepper S, Tjin EP, Vermaelen K, Clark RA, Kupper TS, Luiten RM, Lambert J. First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi. Pigment Cell Melanoma Res 2010; 23:375-84. PubMed
  • Clark RA. Skin-resident T cells: the ups and downs of on site immunity. J Invest Dermatol 2010; 130:362-70. PubMed
  • Clark RA. Regulation gone wrong: a subset of Sézary patients have malignant regulatory T cells. J Invest Dermatol 2009; 129:2747-50. PubMed
  • Huang SJ, Hijnen D, Murphy GF, Kupper TS, Calarese AW, Mollet IG, Schanbacher CF, Miller DM, Schmults CD, Clark RA. Imiquimod Enhances IFN-gamma Production and Effector Function of T Cells Infiltrating Human Squamous Cell Carcinomas of the Skin. J Invest Dermatol 2009; 129:2676-85. PubMed
  • Clark RA, Fuhlbrigge RC. Immunology and skin disease 2009: frontiers in cutaneous immunology. J Invest Dermatol 2009; 129:1849-51. PubMed
  • Clark RA,Huang SJ,Murphy GF,Mollet IG,Hijnen D,Muthukuru M,Schanbacher CF,Edwards V,Miller DM,Kim JE,Lambert J,Kupper TS. Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 2008; 205:2221-34. PubMed
  • Clark RA, Kupper TS. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 2007; 109:194-202. PubMed
  • Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The majority of human peripheral blood CD4+CD25highFoxp3+ regulatory T cells bear functional skin-homing receptors. J Immunol 2006; 177:4488-94. PubMed
  • Clark RA, Chong BF, Mirchandani N, Yamanaka K, Murphy GF, Dowgiert RK, Kupper TS. A novel method for the isolation of skin resident T cells from normal and diseased human skin. J Invest Dermatol 2006; 126:1059-70. PubMed
  • Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, Kupper TS. The vast majority of CLA+ T cells are resident in normal skin. J Immunol 2006; 176:4431-9. PubMed
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