Abstract
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.
Highlights
Modulation of co-inhibitory and co-stimulatory immune checkpoint molecules on tumor-reactive lymphocytes has emerged as a promising therapeutic strategy for a variety of cancers (Hodi et al, 2010; Larkin et al, 2015; Ribas et al, 2015; Robert et al, 2011, 2014, 2015; Weber et al, 2015; Wolchok et al, 2013)
CTLA-4, GITR, ICOS, and OX40 Are Expressed at Highest Density on Tumor-Infiltrating Treg Cells in Mouse and Human CTLA-4 has been described to be constitutively expressed on Treg cells (Read et al, 2000, 2006; Wing et al, 2008) and emerging data suggest this may be relevant to Treg cells infiltrating human tumors (De Simone et al, 2016; Plitas et al, 2016)
We sought to comprehensively evaluate the relative expression of CTLA-4 on circulating and tumorinfiltrating CD4+FoxP3+, CD4+FoxP3À, and CD8+ T lymphocytes across multiple murine models of transplantable syngeneic tumor cell lines of variable immunogenicity, including B16 melanoma, MCA205 sarcoma, MC38 colonic adenocarcinoma, CT26 colorectal carcinoma (Figures 1A–1C), and human solid tumor subtypes including advanced melanoma, early-stage non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) (Figures 1D–1F)
Summary
Modulation of co-inhibitory and co-stimulatory immune checkpoint molecules on tumor-reactive lymphocytes has emerged as a promising therapeutic strategy for a variety of cancers (Hodi et al, 2010; Larkin et al, 2015; Ribas et al, 2015; Robert et al, 2011, 2014, 2015; Weber et al, 2015; Wolchok et al, 2013). Monoclonal antibodies (mAbs) targeting immune checkpoint molecules were initially thought to act solely via regulation of effector T (Teff) cell responses, but recent pre-clinical data in mouse models demonstrates that the activity of certain immune modulatory mAbs (such as anti-CTLA-4, -GITR, and -OX40) may extend beyond simple receptor stimulation or blockade, relying upon an additional capacity to deplete regulatory T (Treg) cells by antibody-dependent cell-mediated cytotoxicity (ADCC) (Bulliard et al, 2013, 2014; Selby et al, 2013; Simpson et al, 2013). This study demonstrates that the activity of anti-CTLA-4 antibodies depends, at least in part, on the depletion of tumor-infiltrating regulatory T (Treg) cells in the context of human FcgRs and human IgGs. Enhanced antibody-dependent cell-mediated cytotoxicity, either by Fc optimization, or the presence of FcgR variants with high binding affinity, improves therapeutic outcomes, but only in highly immunogenic tumors. The same rules may apply to the design of immune modulatory antibodies directed against additional targets with high relative expression on Treg cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
