Low-dose antiangiogenic multikinase inhibitor AL3810 synergizes with PD-1 blockade by reducing CSF1-driven MHC-IIint tumour-associated macrophages to optimize TIM-3+ CD8+ T-cell effector function.
Abstract
Background
AND
Purpose
Antiangiogenic multikinase inhibitors (AAMKIs) with PD-1/PD-L1 blockade have been approved to treat certain solid tumours. Their synergy mechanisms remain largely unknown. AL3810 (lucitanib), a AAMKI in Phase II trials, has demonstrated clinical activity. We aim to elucidate the immune modulatory effects of AL3810 and provide a rationale for its combination with immunotherapy. EXPERIMENTAL APPROACH Murine colorectal cancer models (CT26/MC38) were used. Immunofluorescence/histochemistry, flow cytometry and mass cytometry were used to explore the modulation of AL3810 alone or combined with anti-PD-1 on the tumour microenvironment (TME). Myeloid antigen-presenting cells (APCs) were sorted and co-cultured with pre-activated OT-1 CD8+ T-cells to evaluate their effect on CD8+ T-cell differentiation. KEY
Results
Low-dose AL3810 pruned aberrant vessels and increased pericyte coverage, whereas high-dose caused severe hypoxia and reduced CD8+ T-cell infiltration. Through CSF1R inhibition, low-dose AL3810 reduced MHC-IIint tumour-associated macrophages, which impaired the function and survival of TCF-1-TIM-3+ CD8+ T-cells. Meanwhile it preserved MHC-IIhigh TAMs and conventional dendritic cells, which triggered TCF-1+TIM-3- CD8+ T-cells differentiated into functionally stronger and more viable TCF-1-TIM-3+ CD8+ T-cells. Consistently, the increased expansion and enhanced cytotoxic potential of TCF-1-TIM-3+ CD8+ T-cells underpinned the synergistic antitumour efficacy of low-dose AL3810 combined with αPD-1. Additionally, low-dose AL3810 upregulated co-stimulatory receptors on tumour-infiltrating CD8+ T-cells, providing potential targets to further optimize the regimen.
Conclusions
AND IMPLICATIONS These findings indicate a novel immunomodulatory mechanism of low-dose AL3810, indicating ability to reprogram APC-CD8+ T-cell interactions, a critical axis of immune regulation, supporting its rational combination with PD-1 blockade in CRC treatment.