ABSTRACT
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Melanoma/drug therapy , Polymorphism, Single Nucleotide , Receptors, IgG/genetics , T-Lymphocytes, Regulatory/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological/pharmacology , CTLA-4 Antigen/antagonists & inhibitors , Cell Line, Tumor , Female , Humans , Ipilimumab/administration & dosage , Ipilimumab/pharmacology , Melanoma/genetics , Melanoma/immunology , Mice , Receptors, IgG/metabolism , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
CD25 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.
Subject(s)
Antibodies, Monoclonal/immunology , Immunoglobulin Fc Fragments/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Neoplasms/immunology , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/therapeutic use , Cell Line, Tumor , Flow Cytometry , Humans , Immunotherapy/methods , K562 Cells , Kaplan-Meier Estimate , Lymphocyte Depletion , Mice , Neoplasms/pathology , Neoplasms/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Protein Binding/immunology , Receptors, IgG/immunology , Receptors, IgG/metabolism , T-Lymphocytes, Regulatory/metabolismABSTRACT
In postnatal skin the transcription factor Sox2 is expressed in the dermal papilla (DP) of guard/awl/auchene hair follicles and by mechanosensory Merkel cells in the touch domes of guard hairs. To investigate the consequences of Sox2 ablation in skin we deleted Sox2 in DP cells via Blimp1Cre and in Merkel cells via K14Cre. Loss of Sox2 from the DP did not inhibit hair follicle morphogenesis or establishment of the dermis and hypodermis. However, Sox2 expression in the DP was necessary for postnatal maintenance of awl/auchene hair follicles. Deletion of Sox2 via K14Cre resulted in a decreased number of Merkel cells but had no effect on other epithelial compartments or on the dermis. The reduced number of Merkel cells did not affect the number or patterning of guard hairs, nerve density or the interaction of nerve cells with the touch domes. We conclude that Sox2 is a marker of two distinct lineages in the skin and regulates the number of differentiated cells in the case of the Merkel cell lineage and hair follicle type in the case of the DP.
