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

  • Associate Professor, Dermatology, Harvard Medical School
  • Associate Dermatologist, Dermatology, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Squamous cell carcinomas of the skin (SCC) are a leading cause of death in organ transplant recipients and treatment of non-melanoma skin cancers, of which SCC is the second most frequent type, account for 4.5% of all Medicare cancer costs. The incidence and malignancy of SCC are greatly increased in patients with decreased T cell function, suggesting a role for the immune system in controlling these tumors. T cells are found within SCC but fail to control tumor growth. We have found that SCC evade the immune system at least in part by two newly identified mechanisms. First, by failing to express E-selectin on tumor vessels, SCC evade the population of antigen-experienced skin homing T cells most capable of recognizing the tumor. Second, by recruiting FOXP3+ regulatory T cells (Treg), SCC create a local environment of immune suppression around the tumor. Imiquimod, a TLR7 agonist effective in the treatment of skin cancers, neutralizes both of these defenses, inducing expression of E-selectin on tumor vessels, restoring the ability of CLA+ skin homing T cells to enter the tumor and reducing the % FOXP3+ Treg to levels found in normal skin. Our ongoing studies focus on determining how SCC inhibit vascular E-selectin and recruit Treg with the goal of developing novel agents for the treatment of SCC and their premalignant precursor lesions, actinic keratoses (AK). Additional studies involve determining the mechanisms by which imiquimod induces vascular E-selectin and restores T cell homing, with the goal of developing agents that can treat established SCC without the risk of widespread immune stimulation that is a concern with TLR agonists such as imiquimod. We are currently investigating the hypotheses that nitric oxide (NO) produced by dendritic cells (DC) within SCC inhibit vascular E-selectin and that recruitment of NO-producing DC and Treg both occur via CCR2. We are determining if inhibition of CCR2 function, induction of E-selectin on tumor vessels and inhibition of Treg recruitment can enhance the immunologic response to SCC. These questions are being investigated first in vitro and then in immunodeficient mice grafted with human SCC tumors. Lastly, studies will determine if aberrant homing and Treg recruitment also occur in AK. If so, therapies that induce E-selectin and inhibit recruitment of Treg may be effective in the treatment of these lesions, inducing their immunologic destruction before they progress to SCC. Novel therapies are being evaluated in vitro and in mice grafted with human AK. Our work focuses on the development of novel therapies for squamous cell carcinomas and their premalignant precursor lesions that are safe for use in normal and immunosuppressed individuals. The skin is an accessible tissue in which to study tumor immunity because immune reactions in the skin are visible, easily sampled and can be manipulated with topical medications. Because impaired T cell homing and recruitment of regulatory T cells occur in many human malignancies, findings and novel therapies arising from this work should be applicable to the treatment of other types of human cancer.

 

Publications

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  • 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 2013. 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 留硫 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 S辿zary 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 2006; 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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