Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma

Abstract

Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3 + regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3 + Tregs by diphtheria toxin injection, we observed that transient Foxp3 + Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-g and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4 + and CD8 + T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3 + Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.

Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy

“…Hence, there is significant interest in developing combinatorial strategies to enhance systemic antitumor immune responses that involve Tregs. Depletion of Tregs using genetic approaches promotes antitumor immunity following irradiation of preclinical models of mesothelioma [ 190 ]. Similarly, GITR agonizts and PI3Kαδ inhibitors that deplete Treg numbers promoted the antitumor efficacy of radiation exposure in multiple models [ 191 , 192 ].…”

The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review

“…Indeed, in this in vivo model, the removal of these cells using a CD-25 depleting antibody improved the median survival from 19 to 33 days [33]. In addition, in patients with resectable MPM included in the SMART trial (Surgery for Mesothelioma after Radiation Therapy) [85] evaluating a short, accelerated course of high-dose hemithoracic intensity-modulated radiation therapy followed by extrapleural pneumonectomy, FOXP3+ Tregs were found to be increased after irradiation and, thus, could contribute to limiting its efficiency [86]. More interestingly, in a transgenic DEREG xenograft model (selective depletion of Tregs using diphtheria toxin injection), the transient depletion of FOXP3+ Tregs, following nonablative oligofractionated irradiation, improved the anti-tumour effect.…”

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

“…However, exposure to RT triggers various immunosuppressive mechanisms, including the recruitment of regulatory T (Treg) cells [ 76 ], M2 macrophages, and myeloid-derived suppressor cells (MDSCs) [ 36 ]. Moreover, RT contributes to the generation and activation of cancer-associated fibroblasts that provide immunosuppressive cytokine signaling [ 77 ].…”

“…The mechanisms underlying RT-associated immune modulation have been exhaustively described in recent studies (reviewed in [75]) and include, as previously highlighted, immuno-stimulating pathways involved in the immuno-mediated abscopal effect. However, exposure to RT triggers various immunosuppressive mechanisms, including the recruitment of regulatory T (Treg) cells [76], M2 macrophages, and myeloid-derived suppressor cells (MDSCs) [36]. Moreover, RT contributes to the generation and activation of cancer-associated fibroblasts that provide immunosuppressive cytokine signaling [77].…”