SummaryWith 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.

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.

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IMPORTANCE Rituximab induces B-lymphocyte apoptosis by targeting CD20 antigen and has shown efficacy in antibody-mediated autoimmune disease. Rituximab is increasingly being acknowledged as an effective and safe treatment option for pemphigus.OBJECTIVE To assess the clinical response of patients with pemphigus to rituximab using a modified fixed-dose rheumatoid arthritis protocol (1 g intravenously on days 1 and 15, followed by 500 mg intravenously if clinically warranted at 6-month intervals or repeated full dosing). DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study was conducted using records from a tertiary referral center for autoimmune bullous disorders. Participants included 92 patients (pemphigus vulgaris, 84 [91%], and pemphigus foliaceus, 8 [9%]) who

Association of specific miRNAs with clinicopathological features indicates their biological relevance and highlights the power of ANN to reliably predict clinically relevant miRNA biomarkers, which it is hoped will better stratify patients to guide adjuvant therapy.