Transient Treg depletion enhances therapeutic anti‐cancer vaccination

Abstract

IntroductionRegulatory T cells (Treg) play an important role in suppressing anti‐ immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti‐cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg.MethodsTumor bearing BALB/c FoxP3.dtr transgenic mice were subjected to different treatment protocols, with or without Treg depletion and tumor growth and survival monitored.ResultsDTX specifically depleted Treg in a transient, dose‐dependent manner. Treg depletion correlated with delayed tumor growth, increased effector T cell (Teff) activation, and enhanced survival in a range of solid tumors. Tumor regression was dependent on Teffs as depletion of both CD4 and CD8 T cells completely abrogated any survival benefit. Severe morbidity following Treg depletion was only observed, when consecutive doses of DTX were given during peak CD8 T cell activation, demonstrating that Treg can be depleted on multiple occasions, but only when CD8 T cell activation has returned to base line levels. Finally, we show that even minimal Treg depletion is sufficient to significantly improve the efficacy of tumor‐peptide vaccination.ConclusionsBALB/c.FoxP3.dtr mice are an ideal model to investigate the full therapeutic potential of Treg depletion to boost anti‐tumor immunity. DTX‐mediated Treg depletion is transient, dose‐dependent, and leads to strong anti‐tumor immunity and complete tumor regression at high doses, while enhancing the efficacy of tumor‐specific vaccination at low doses. Together this data highlight the importance of Treg manipulation as a useful strategy for enhancing current and future cancer immunotherapies.

The multifaceted Foxp3fgfp allele enhances spontaneous and therapeutic immune surveillance of cancer in mice

“…The last phase of tumor progression is metastatic dissemination, a process well modelled by the 4T1 breast carcinoma derived from a BALB/c mouse. A moderate role for Treg in facilitating 4T1 primary tumor growth and precipitating death has been reported. Monitoring WT and Foxp3‐fGFP animals implanted subcutaneously with 4T1 cells revealed similar growth of the primary tumor while survival was significantly prolonged in the latter group (Fig.…”

PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

“…FCM was used to detect the T‐cell subsets. As shown in Figures a – c , the proportions of different T‐cell subsets in the blood were measured by FCM. The proportions of CD4 + and CD8 + T‐cells in the combined group were the highest among the four groups ( p < 0.05; Fig.…”

“…Recurrence of solid tumors may be due to the inability of traditional chemotherapy and radiotherapy to eliminate CSCs . At present, therapeutic vaccines have been extensively used to induce endogenous tumor‐reactive T cells . We have developed a technology that immobilizes streptavidin (SA)‐tagged bioactive cytokines on the biotinylated tumor cell surface to prepare tumor cell vaccines.…”

Immunotherapy for Breast Cancer: Current and Future Strategies

“…Studies in animals have demonstrated the ability Treg depletion to synergize with immunotherapy in a murine model of mesothelioma [84]. Importantly, studies investigating the utility of targeting Tregs in cancer patients identified a novel mechanism by which the administration of FDA-approved daclizumab, a monoclonal antibody which specifically targets CD25, selectively reprogrammed Tregs to produce IFN-gamma by driving the downregulation of FoxP3; this resulted in robust T cell responses against vaccine antigens without autoimmunity [85, 86].…”