Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

TLDR

CTLA‑4 is a key negative regulator of immune responses, whose loss causes fatal lymphoproliferative disease, and while anti‑CTLA‑4 antibodies show efficacy in melanoma, the primary cellular target remains unclear. The study aimed to determine whether effector or regulatory T cells are the critical target of anti‑CTLA‑4 antibody therapy. Using a human‑CTLA‑4 knock‑in mouse model of melanoma, the authors independently blocked CTLA‑4 on effector or regulatory T cells to assess their individual contributions to antitumor immunity. Blockade of CTLA‑4 on effector T cells alone modestly improved tumor protection, whereas blocking only regulatory T cells had no effect, but simultaneous blockade of both compartments produced a synergistic, maximal antitumor response.

Abstract

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (Teff) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti–CTLA-4 antibodies during cancer immunotherapy.