Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells

By M. Selby, John Engelhardt, M. Quigley, Karla A. Henning, Timothy Chen, M. Srinivasan, A. Korman. Cancer immunology research, 2013

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The therapeutic potential of CTLA-4 blockade is evident in the ability of anti-CTLA-4 antibody to induce regression of established tumors. In an elegant set of experiments using a panel of murine immunoglobulin in various isotypes, Selby and colleagues delineated the mechanism of action of CTLA-4 blockade. Anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral T-regulatory cells along with concomitant activation of T-effector cells. Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine immunoglobulin G (IgG)2a constant region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b constant region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8+ Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. Cancer Immunol Res; 1(1); 32–42. ©2013 AACR.

Subfields: Immunology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/c29e93dc4057d8fa37c0bd65fefa924685ccac09

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Citations in the corpus

• Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells (2016, background): “Recent experimental evidence shows that anti-CTLA-4 mAb efficacy depends on FcgR-mediated depletion of CD4+ regulatory T cells (Treg cells) within the tumor microenvironment (Peggs et al., 2009; Selby et al., 2013; Simpson et al., 2013; TwymanSaint Victor et al., 2015).”