Abstract
SummaryCD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
Highlights
Regulatory T (Treg) cells are generally regarded as one of the major obstacles to the successful clinical application of tumor immunotherapy
CD25 expression appeared consistent across multiple models of transplantable tumor cell lines of variable immunogenicity including MCA205 sarcoma, MC38 colon adenocarcinoma, B16 melanoma, and CT26 colorectal carcinoma, with a higher percentage of CD25-expressing CD4+forkhead box P3 (FoxP3)+ Treg cells relative to CD4+FoxP3À and CD8+ Teff cells (Figure 1A)
Teff cell compartment was observed in vivo and the percentage of CD25-expressing Teff cells (CD8+ = 3.08%–8.35%, CD4+FoxP3À = 14.11%–26.87%) was significantly lower than on Treg cells (83.66%–90.23%) (p < 0.001) (Figure 1B)
Summary
Regulatory T (Treg) cells are generally regarded as one of the major obstacles to the successful clinical application of tumor immunotherapy. Defining appropriate targets for selective interference with Treg cells is a critical step in the development of effective therapies In this regard, CD25, known as the interleukin-2 high-affinity receptor alpha chain (IL-2Ra), was the first surface marker used to identify and isolate Treg cells (Sakaguchi et al, 1995) prior to the discovery of their master regulator, transcription factor forkhead box P3 (FoxP3). CD25, known as the interleukin-2 high-affinity receptor alpha chain (IL-2Ra), was the first surface marker used to identify and isolate Treg cells (Sakaguchi et al, 1995) prior to the discovery of their master regulator, transcription factor forkhead box P3 (FoxP3) It is the most extensively studied target for mediating Treg cell depletion. Whereas CD25 is constitutively expressed on Treg cells and absent on naive Teff cells, transient upregulation has been described upon activation of Teff cells, these observations derive largely from in vitro studies (Boyman and Sprent, 2012)
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