Tuesday, April 29, 2025
4/29/2025
Characterization of an inflammasome-unleashing approach to improve anti-PD-1 therapy in cancer - ABSTRACT Blockade of the immune checkpoint PD-1/PD-L1 has increased overall and progression-free survival in various cancers. However, only a restricted number of patients show clinical benefits. Understanding the mechanisms by which anti-PD-1 antibodies modulate exhausted CD8+ T cells is mandatory to improve this approach. In this context, the role played by inflammation in T cell exhaustion and tumor immunotherapy is controversial. Observations on various mouse models and on human melanoma cohorts support the notion that activation of innate immune players such as inflammasomes, may play a key role in anti-PD-1 therapy. However, we need to identify molecular targets to trigger inflammasome activation potentially leading to improved anti-PD-1 therapy. TMEM176B is an intracellular cation channel strongly expressed by conventional type 2 dendritic cells (cDC2) that inhibits inflammasome activation through ionic mechanisms. Boritinib, a potent TMEM176B inhibitor, induced tumor growth control and reinforced the antitumor activity of anti-PD-1 antibodies in a Tmem176b, inflammasome and CD8+ T cell-dependent manner in lymphoma, melanoma, lung and colon mouse cancer models. However, the mechanism underlying CD8+ T cell reinforcement remains unknown. This project aims at characterizing the mechanisms by which Boritinib improves anti-PD-1 therapy, setting the ground for the clinical evaluation of the compound. Our published and unpublished results led us to propose that inflammasome activation triggered by Boritinib therapy may modulate subsets of exhausted CD8+ T cells, through a mechanism involving Th17 cells. We will carry out a research program involving functional in vivo studies and bioinformatics analysis based on three specific aims. In Specific Aim 1 we wish to confirm and complement our unpublished results suggesting that Boritinib modulates CD8+ T cell exhaustion. In specific aim 2 we will then assess whether Th17 cells are Boritinib/inflammasome-triggered effectors leading to modulation of exhausted CD8+ T cells. In Specific Aim 3 we will study the impact of timing when combining both therapies. We speculate that the timing at which anti-PD-1 therapy and inflammasome modulation occur might determine the fate of exhausted CD8+ T cells and, perhaps, the clinical outcome of immunotherapeutic modalities. On this basis, future research will then complete ongoing preclinical pharmacological characterization of Boritinib before engaging a clinical study of the compound. This knowledge may position Boritinib as a potential candidate to be a first-in-class drug in immuno- oncology.
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