Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

Christel Devaud; Jennifer A Westwood; Michele Wl Teng; Liza B John; Carmen Sm Yong; Connie Pm Duong; Mark J Smyth; Phillip K Darcy; Michael H Kershaw

doi:10.4161/21624011.2014.963395

Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors

Oncoimmunology. 2014 Dec 21;3(11):e963395. doi: 10.4161/21624011.2014.963395. eCollection 2014 Nov.

Authors

Christel Devaud¹, Jennifer A Westwood¹, Michele Wl Teng², Liza B John¹, Carmen Sm Yong¹, Connie Pm Duong¹, Mark J Smyth³, Phillip K Darcy⁴, Michael H Kershaw⁴

Affiliations

¹ Cancer Immunology Research Program; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, Victoria, Australia.
² Cancer Immune Regulation and Immunotherapy Laboratory; QIMR Berghofer Medical Research Institute ; Brisbane, Queensland, Australia.
³ Immunology in Cancer and Infection Laboratory; QIMR Berghofer Medical Research Institute ; Brisbane, Queensland, Australia.
⁴ Cancer Immunology Research Program; Sir Peter MacCallum Department of Oncology; University of Melbourne ; Parkville, Victoria, Australia ; Department of Immunology; Monash University ; Prahran, Victoria, Australia.

Abstract

In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3^DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8⁺ effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4⁺ T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.

Keywords: CD, cluster of differentiation; CTLA-4, cytotoxic T lymphocyte antigen 4; DEREG, Depletion of Regulatory T cells; DT, diphtheria toxin; DTR, diphtheria toxin receptor; FCS, fetal calf serum; FR, folate receptor; Foxp3, Forkhead box protein P3; IFN, interferon; IK, intra-kidney; IL, interleukin; IP, intra-peritoneal; IV, intravenously; M2, type-2 immunosuppressive macrophages; PBS, phosphate-buffered saline; PD-1, program cell death protein 1; PD-L1, PD ligand 1; Renca Ch+ L+, Renca Cherry Luciferase; SC, subcutaneous; T regulatory cells; TCR, T cell receptor; Th, T helper cells; Treg, regulatory T cells; depletion; immunosuppression; kidney tumors; mAb, monoclonal antibody; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't