Journal Article
. 2017 May; 8(29):47440-47453.
doi: 10.18632/oncotarget.17663.

Intratumoral depletion of regulatory T cells using CD25-targeted photodynamic therapy in a mouse melanoma model induces antitumoral immune responses

Dong Sun Oh 1 Heegon Kim 2 Ji Eun Oh 3 Hi Eun Jung 1 Yun Soo Lee 2 Ji-Ho Park 2 Heung Kyu Lee 1 
  • PMID: 28537894
  •     41 References
  •     14 citations


Tumor immunotherapy aims to overcome the immunosuppressive microenvironment within tumors, and various approaches have been developed. Tumor-associated T regulatory cells (Tregs) suppress the activation and expansion of tumor antigen-specific effector T cells, thus, providing a permissive environment for tumor growth. Therefore, optimal strategies need to be established to deplete tumor-infiltrated Tregs because systemic depletion of Tregs can result in reduced anti-tumor effector cells and autoimmunity. Here, to selectively deplete Tregs in tumors, we intratumorally injected anti-CD25 antibodies conjugated to Chlorin e6 (Ce6), a photosensitizer that absorbs light to generate reactive oxygen species. Local depletion of tumor-associated Tregs with photodynamic therapy (PDT) inhibited tumor growth, which was likely due to the altered tumor immune microenvironment that was characterized by increased infiltration of CD8+ effector T cells and the expression of IFN-γ and CD107a, which is a cytolytic granule exocytosis marker in tumor tissues. Furthermore, PDT-induced intratumoral Treg depletion did not influence adaptive immune responses in a murine influenza infection model. Thus, our results show that intratumoral Treg-targeted PDT could specifically modulate tumor microenvironments by depleting Tregs and could be used as a novel cancer immunotherapy technique.

Keywords: CD25; Chlorin e6; Treg; immunotherapy; photodynamic therapy.

Ability of specific monoclonal antibodies and conventional antisera conjugated to hematoporphyrin to label and kill selected cell lines subsequent to light activation.
D Mew, V Lum, +6 authors, J G Levy.
Cancer Res, 1985 Sep 01; 45(9). PMID: 4028022
Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo.
Mei-Ling Chen, Mikaël J Pittet, +4 authors, Khashayarsha Khazaie.
Proc Natl Acad Sci U S A, 2004 Dec 30; 102(2). PMID: 15623559    Free PMC article.
Highly Cited.
Cancer immunotherapy--the endgame begins.
Louis M Weiner.
N Engl J Med, 2008 Jun 21; 358(25). PMID: 18565858    Free PMC article.
Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy.
Mario P Colombo, Silvia Piconese.
Nat Rev Cancer, 2007 Oct 25; 7(11). PMID: 17957190
Highly Cited. Review.
Regulatory T cells in cancer immunotherapy.
Hiroyoshi Nishikawa, Shimon Sakaguchi.
Curr Opin Immunol, 2014 Jan 15; 27. PMID: 24413387
Highly Cited. Review.
Photodynamic therapy and anti-tumour immunity.
Ana P Castano, Pawel Mroz, Michael R Hamblin.
Nat Rev Cancer, 2006 Jun 24; 6(7). PMID: 16794636    Free PMC article.
Highly Cited. Review.
Combination cancer immunotherapies tailored to the tumour microenvironment.
Mark J Smyth, Shin Foong Ngiow, Antoni Ribas, Michele W L Teng.
Nat Rev Clin Oncol, 2015 Nov 26; 13(3). PMID: 26598942
Highly Cited. Review.
Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa.
Ji Eun Oh, Byoung-Chan Kim, +8 authors, Heung Kyu Lee.
Proc Natl Acad Sci U S A, 2016 Jan 27; 113(6). PMID: 26811463    Free PMC article.
The future of immune checkpoint therapy.
Padmanee Sharma, James P Allison.
Science, 2015 Apr 04; 348(6230). PMID: 25838373
Highly Cited. Review.
Folic Acid-conjugated Graphene Oxide loaded with Photosensitizers for Targeting Photodynamic Therapy.
Peng Huang, Cheng Xu, +6 authors, Daxiang Cui.
Theranostics, 2011 May 13; 1. PMID: 21562631    Free PMC article.
Highly Cited.
Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy.
Kazuhide Sato, Noriko Sato, +5 authors, Hisataka Kobayashi.
Sci Transl Med, 2016 Aug 19; 8(352). PMID: 27535621    Free PMC article.
Cancer immunotherapy comes of age.
Steven A Rosenberg.
Nat Clin Pract Oncol, 2005 Nov 03; 2(3). PMID: 16264884    Free PMC article.
T-cell quality in memory and protection: implications for vaccine design.
Robert A Seder, Patricia A Darrah, Mario Roederer.
Nat Rev Immunol, 2008 Mar 08; 8(4). PMID: 18323851
Highly Cited. Review.
The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells.
Dennis Lindau, Paul Gielen, +2 authors, Gosse J Adema.
Immunology, 2012 Dec 12; 138(2). PMID: 23216602    Free PMC article.
Highly Cited. Review.
CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients.
Andrew J Rech, Rosemarie Mick, +13 authors, Robert H Vonderheide.
Sci Transl Med, 2012 May 18; 4(134). PMID: 22593175    Free PMC article.
Highly Cited.
CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.
Jianda Yuan, Sacha Gnjatic, +17 authors, Jedd D Wolchok.
Proc Natl Acad Sci U S A, 2008 Dec 17; 105(51). PMID: 19074257    Free PMC article.
Highly Cited.
Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.
Sameer A Siddiqui, Xavier Frigola, +13 authors, Eugene D Kwon.
Clin Cancer Res, 2007 Apr 04; 13(7). PMID: 17404089
Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens.
Richard W Childs, Mattias Carlsten.
Nat Rev Drug Discov, 2015 May 23; 14(7). PMID: 26000725
Highly Cited. Review.
Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
Makoto Miyara, Yumiko Yoshioka, +15 authors, Shimon Sakaguchi.
Immunity, 2009 May 26; 30(6). PMID: 19464196
Highly Cited.
Enhancement of anti-tumor immunity by photodynamic therapy.
Sandra O Gollnick, Craig M Brackett.
Immunol Res, 2009 Sep 19; 46(1-3). PMID: 19763892    Free PMC article.
Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis.
Masashi Sakaki, Kazumasa Hiroishi, +6 authors, Michio Imawari.
Hepatol Res, 2007 Nov 21; 38(4). PMID: 18021223
The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer.
Khashayarsha Khazaie, Harald von Boehmer.
Semin Cancer Biol, 2006 Jan 31; 16(2). PMID: 16443370
CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity.
Xin Chen, Yong Du, Zhiming Huang.
Immunol Lett, 2012 Sep 25; 148(1). PMID: 23000301
Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules.
Makoto Mitsunaga, Mikako Ogawa, +3 authors, Hisataka Kobayashi.
Nat Med, 2011 Nov 08; 17(12). PMID: 22057348    Free PMC article.
Highly Cited.
Photosensitizer-conjugated silica-coated gold nanoclusters for fluorescence imaging-guided photodynamic therapy.
Peng Huang, Jing Lin, +9 authors, Xiaoyuan Chen.
Biomaterials, 2013 Mar 26; 34(19). PMID: 23523428    Free PMC article.
TRAIL suppresses tumor growth in mice by inducing tumor-infiltrating CD4(+)CD25 (+) Treg apoptosis.
Zhijuan Diao, Juan Shi, +5 authors, Dexian Zheng.
Cancer Immunol Immunother, 2012 Nov 13; 62(4). PMID: 23143747
Efficient Treg depletion induces T-cell infiltration and rejection of large tumors.
Xingrui Li, Efterpi Kostareli, +2 authors, Günter J Hämmerling.
Eur J Immunol, 2010 Nov 13; 40(12). PMID: 21072887
Homeostatic control of regulatory T cell diversity.
Adrian Liston, Daniel H D Gray.
Nat Rev Immunol, 2014 Feb 01; 14(3). PMID: 24481337
Highly Cited. Review.
Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody.
S Onizuka, I Tawara, +3 authors, E Nakayama.
Cancer Res, 1999 Jul 09; 59(13). PMID: 10397255
Highly Cited.
Regulatory T-cell therapy: is it ready for the clinic?
Jeffrey A Bluestone.
Nat Rev Immunol, 2005 Mar 19; 5(4). PMID: 15775994
A review of progress in clinical photodynamic therapy.
Z Huang.
Technol Cancer Res Treat, 2005 May 18; 4(3). PMID: 15896084    Free PMC article.
Highly Cited. Review.
Oncology meets immunology: the cancer-immunity cycle.
Daniel S Chen, Ira Mellman.
Immunity, 2013 Jul 31; 39(1). PMID: 23890059
Highly Cited. Review.
Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.
Shimon Sakaguchi, Masahiro Ono, +6 authors, Takashi Nomura.
Immunol Rev, 2006 Aug 15; 212. PMID: 16903903
Highly Cited. Review.
How do regulatory T cells work?
A Corthay.
Scand J Immunol, 2009 Sep 16; 70(4). PMID: 19751267    Free PMC article.
Highly Cited. Review.
Regulatory T cells exert checks and balances on self tolerance and autoimmunity.
Kajsa Wing, Shimon Sakaguchi.
Nat Immunol, 2009 Dec 18; 11(1). PMID: 20016504
Highly Cited. Review.
Caspase-1 independent viral clearance and adaptive immunity against mucosal respiratory syncytial virus infection.
Ye Ri Shim, Heung Kyu Lee.
Immune Netw, 2015 Apr 30; 15(2). PMID: 25922596    Free PMC article.
CD8+ T cell efficacy in vaccination and disease.
Victor Appay, Daniel C Douek, David A Price.
Nat Med, 2008 Jun 07; 14(6). PMID: 18535580
Highly Cited. Review.
Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune diseases in wild-type and B-cell-deficient NOD mice.
Jason S Ellis, Xiaoxiao Wan, Helen Braley-Mullen.
Immunology, 2013 Jan 09; 139(2). PMID: 23293979    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis.
Alice McNally, Geoffrey R Hill, +2 authors, Raymond J Steptoe.
Proc Natl Acad Sci U S A, 2011 Apr 20; 108(18). PMID: 21502514    Free PMC article.
Depleting tumor-specific Tregs at a single site eradicates disseminated tumors.
Aurélien Marabelle, Holbrook Kohrt, +13 authors, Ronald Levy.
J Clin Invest, 2013 Jun 04; 123(6). PMID: 23728179    Free PMC article.
Highly Cited.
The role and significance of VEGFR2+ regulatory T cells in tumor immunity.
Panrong Zhu, Chenxi Hu, Kaiyuan Hui, Xiaodong Jiang.
Onco Targets Ther, 2017 Sep 19; 10. PMID: 28919780    Free PMC article.
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality.
Il-Kug Kim, Kangsan Kim, +17 authors, Injune Kim.
J Exp Med, 2018 Feb 16; 215(3). PMID: 29444818    Free PMC article.
Antisense oligonucleotide targeting CD39 improves anti-tumor T cell immunity.
Abhishek S Kashyap, Tamara Thelemann, +8 authors, Alfred Zippelius.
J Immunother Cancer, 2019 Mar 16; 7(1). PMID: 30871609    Free PMC article.
Susceptibility and Resistance Mechanisms During Photodynamic Therapy of Melanoma.
Xin-Ying Li, Liu-Chang Tan, +5 authors, Yuan-Gang Lu.
Front Oncol, 2020 Jun 13; 10. PMID: 32528867    Free PMC article.
Photodynamic Therapy and Immunity: An Update.
Riddhi Falk-Mahapatra, Sandra O Gollnick.
Photochem Photobiol, 2020 Mar 05; 96(3). PMID: 32128821    Free PMC article.
CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity.
Francesca Zammarchi, Karin Havenith, +3 authors, Patrick H van Berkel.
J Immunother Cancer, 2020 Sep 12; 8(2). PMID: 32912922    Free PMC article.
Hyper-Progressive Disease: The Potential Role and Consequences of T-Regulatory Cells Foiling Anti-PD-1 Cancer Immunotherapy.
Christopher Tay, Yamin Qian, Shimon Sakaguchi.
Cancers (Basel), 2020 Dec 31; 13(1). PMID: 33375291    Free PMC article.
Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors.
Jang Hyun Park, Hyun-Jin Kim, +10 authors, Heung Kyu Lee.
Nat Immunol, 2021 Feb 13; 22(3). PMID: 33574616
Reducing the immunosuppressive tumor microenvironment enhances photoimmunotherapy efficacy.
Mouldy Sioud.
EBioMedicine, 2021 May 10; 67. PMID: 33965875    Free PMC article.
Current Prospects for Treatment of Solid Tumors via Photodynamic, Photothermal, or Ionizing Radiation Therapies Combined with Immune Checkpoint Inhibition (A Review).
Sanjay Anand, Timothy A Chan, Tayyaba Hasan, Edward V Maytin.
Pharmaceuticals (Basel), 2021 Jun 03; 14(5). PMID: 34068491    Free PMC article.
Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer.
Daniel R Principe, Lauren Chiec, Nisha A Mohindra, Hidayatullah G Munshi.
Front Oncol, 2021 Jun 19; 11. PMID: 34141625    Free PMC article.
Evaluation of In Vitro Phototoxicity of a Minibody-IR700 Conjugate Using Cell Monolayer and Multicellular Tumor Spheroid Models.
Mouldy Sioud, Petras Juzenas, +2 authors, Qian Peng.
Cancers (Basel), 2021 Jul 21; 13(13). PMID: 34283089    Free PMC article.
Inhibition of photodynamic therapy induced-immunosuppression with aminolevulinic acid leads to enhanced outcomes of tumors and pre-cancerous lesions.
Sharlo Bayless, Jeffrey B Travers, Ravi P Sahu, Craig A Rohan.
Oncol Lett, 2021 Aug 14; 22(3). PMID: 34386086    Free PMC article.
Nanoparticle-Based Drug Delivery Systems for Photodynamic Therapy of Metastatic Melanoma: A Review.
Nkune Williams Nkune, Heidi Abrahamse.
Int J Mol Sci, 2021 Nov 28; 22(22). PMID: 34830431    Free PMC article.