Venetoclax Induces BCL-2-Dependent Treg to TH17 Plasticity to Enhance the Antitumor Efficacy of Anti-PD-1 Checkpoint Blockade

Cancer Immunol Res. 2024 Aug 1;12(8):1074-1089. doi: 10.1158/2326-6066.CIR-23-0344.

Abstract

The specific BCL-2 small molecule inhibitor venetoclax induces apoptosis in a wide range of malignancies, which has led to rapid clinical expansion in its use alone and in combination with chemotherapy and immune-based therapies against a myriad of cancer types. While lymphocytes, and T cells in particular, rely heavily on BCL-2 for survival and function, the effects of small molecule blockade of the BCL-2 family on surviving immune cells is not fully understood. We aimed to better understand the effect of systemic treatment with venetoclax on regulatory T cells (Treg), which are relatively resistant to cell death induced by specific drugging of BCL-2 compared to other T cells. We found that BCL-2 blockade altered Treg transcriptional profiles and mediated Treg plasticity toward a TH17-like Treg phenotype, resulting in increased IL17A production in lymphoid organs and within the tumor microenvironment. Aligned with previously described augmented antitumor effects observed when combining venetoclax with anti-PD-1 checkpoint inhibition, we also demonstrated that Treg-specific genetic BCL-2 knockout combined with anti-PD-1 induced tumor regression and conferred overlapping genetic changes with venetoclax-treated Tregs. As long-term combination therapies using venetoclax gain more traction in the clinic, an improved understanding of the immune-modulatory effects caused by venetoclax may allow expansion of its use against malignancies and immune-related diseases.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Bridged Bicyclo Compounds, Heterocyclic* / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic* / therapeutic use
  • Cell Line, Tumor
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2* / genetics
  • Proto-Oncogene Proteins c-bcl-2* / metabolism
  • Sulfonamides* / pharmacology
  • Sulfonamides* / therapeutic use
  • T-Lymphocytes, Regulatory* / drug effects
  • T-Lymphocytes, Regulatory* / immunology
  • Th17 Cells* / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • venetoclax
  • Sulfonamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Proto-Oncogene Proteins c-bcl-2
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Antineoplastic Agents