Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade?

Abstract

Antibodies to human CTLA-4 have been shown to induce long-lasting protection against melanoma. It is assumed that these antibodies cause tumor rejection by blocking negative signaling from the B7-CTLA-4 interactions to enhance priming of naïve T cells in the lymphoid organs. Recently, we reported that anti-CTLA-4 antibody Ipilimumab effectively induces tumor rejection in vivo although it blocks neither B7 transendocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Using genetic model in which the anti-CTLA-4 antibodies are unable to engage more than 50% of CTLA-4, we demonstrated that saturating binding of CTLA-4 is not necessary for tumor rejection. Our results argue against B7-CTLA-4 blockade as the mechanism of action for the clinically effective Ipilimumab. Moreover, Ipilimumab induces tumor rejection even in the absence of de novo T cell priming in the lymphoid organs. Thus, our data are inconsistent with key provisions of the prevailing hypothesis on mechanism of action by anti-CTLA-4 antibodies. Furthermore, anti-CTLA-4 antibodies effectively induce depletion of regulatory T (Treg) cells in tumor microenvironment but not in the peripheral lymphoid organs, which is strictly dependent on Fc receptor on host cells. Based on these data and other recent publications on the subject, we propose that anti-human CTLA-4 antibodies induce tumor rejection by selective depletion of Tregs in the tumors rather than blockade of B7-CTLA-4 interaction in lymphoid organs.

Keywords: B7-CTLA-4 interaction; CTLA-4; Cancer immunotherapy; Ipilimumab; Regulatory T cells; Tumor microenvironment.

Fig. 1

The prevailing view: CTLA-4 checkpoint blockade results in tumor immunity. Activation of T cells requires two signals. One is the binding of the T cell receptor (TCR) to the MHC-antigen peptide complex presented by antigen presenting cells (APCs) (signal 1). The other one is the binding of B7 molecules (B7-1 or B7-2) to the co-stimulatory (+) molecule CD28 on the surface of T cells (signal 2). With higher affinity than CD28, inhibitory (−) CTLA-4 binds to B7 ligands on APCs and provides a brake  for T cell activation. Anti-CTLA-4 antibodies were proposed to release brakes of naïve T cells and allow them to be activated in the lymphoid organs and then migrate to tumors to cause tumor rejection

Fig. 2

New concept: selective depletion of Tregs in the tumor microenvironment results in tumor immunity. Higher levels of CTLA-4 on intratumoral Tregs allow their selective depletion by anti-CTLA-4 antibodies, perhaps through antibody-dependent cellular phagocytosis (ADCP) by macrophages and/or antibody-dependent cellular cytotoxicity (ADCC) by NK cells. Blocking of B7-CTLA-4 interaction is not required for effective depletion of intratumoral Treg cells