Fattori et al. re-analyzed public scRNA datasets to study the role of Treg subsets in PD-1 blockade-resistant early, advanced, and metastatic TNBC. The TME of primary and metastatic TNBC was enriched in highly suppressive 4-1BB+CD25high effector Tregs (eTregs) that persisted following PD-1 blockade and were associated with decreased survival. In a syngeneic TNBC model, anti-PD-1 synergized with an IL-2-sparing CD25 mAb to deplete eTregs (CD25 was identified as the most selective eTreg target in TNBC) resulting in enhanced antitumor immunity and survival, and an increased αβCD8+ T cell/Treg ratio in tumors and the periphery.
Contributed by Katherine Turner
ABSTRACT: Regulatory T cells (Tregs) impede effective antitumor immunity. However, the role of Tregs in clinical outcomes of patients with triple-negative breast cancer (TNBC) remains controversial. Here, we found that an immunosuppressive TNBC microenvironment is marked by an imbalance between effector αβCD8+ T cells and Tregs harboring hallmarks of highly suppressive effector Tregs (eTregs). Intratumoral eTregs strongly expressed PD-1 and persisted in patients with TNBC resistant to PD-1 blockade. Importantly, CD25 was the most selective surface marker of eTregs in primary TNBC and metastases compared with other candidate targets for eTreg depletion currently being evaluated in trials for patients with advanced TNBC. In a syngeneic TNBC model, the use of Fc-optimized, IL-2 sparing, anti-CD25 antibodies synergized with PD-1 blockade to promote systemic antitumor immunity and durable tumor growth control by increasing effector αβCD8+ T cell/Treg ratios in tumors and in the periphery. Together, this study provides the rationale for clinical translation of anti-CD25 therapy to improve PD-1 blockade responses in patients with TNBC.
Author Info: (1) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (2) Alderaan Biotechnology, Paris, France. (3) Alderaan Biotechnology, Paris, France. (4) Centre de Recherc
Author Info: (1) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (2) Alderaan Biotechnology, Paris, France. (3) Alderaan Biotechnology, Paris, France. (4) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (5) Alderaan Biotechnology, Paris, France. (6) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (7) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (8) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (9) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (10) Centre de Recherche en Cancérologie de Marseille, Marseille, France. (11) Institute Paoli-Calmettes, Marseille, France. (12) Institute Paoli-Calmettes, Marseille, France. (13) Institute Paoli-Calmettes, Marseille, France. (14) Institute Paoli-Calmettes, Marseille, France. (15) Institute Paoli-Calmettes, Marseille, France. (16) Institute Paoli-Calmettes, Marseille, France. (17) Institute Paoli-Calmettes, Marseille, France. (18) Institute Paoli-Calmettes, marseille, France. (19) Alderaan Biotechnology, Paris, France. (20) Inserm, Marseille, France. (21) Institute Paoli-Calmettes, Marseille, France.
