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Differential potency of regulatory T cell-mediated immunosuppression in kidney tumors compared to subcutaneous tumors
journal contribution
posted on 2023-10-24, 05:05 authored by C Devaud, J A Westwood, M W L Teng, L B John, C S M Yong, C P M Duong, M J Smyth, P K Darcy, M H KershawIn 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 Foxp3DTR 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.
History
Journal
OncoImmunologyVolume
3Pagination
e963395-1-e963395-10 - ?Publisher DOI
ISSN
2162-4011eISSN
2162-402XPublication classification
C1.1 Refereed article in a scholarly journalUsage metrics
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Keywords
CD, cluster of differentiationCTLA-4, cytotoxic T lymphocyte antigen 4DEREG, Depletion of Regulatory T cellsDT, diphtheria toxinDTR, diphtheria toxin receptorFCS, fetal calf serumFR, folate receptorFoxp3, Forkhead box protein P3IFN, interferonIK, intra-kidneyIL, interleukinIP, intra-peritonealIV, intravenouslyM2, type-2 immunosuppressive macrophagesPBS, phosphate-buffered salinePD-1, program cell death protein 1PD-L1, PD ligand 1Renca Ch+ L+, Renca Cherry LuciferaseSC, subcutaneousT regulatory cellsTCR, T cell receptorTh, T helper cellsTreg, regulatory T cellsdepletionimmunosuppressionkidney tumorsmAb, monoclonal antibodytumor microenvironmentImmunology
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