Low‐dose antiangiogenic multikinase inhibitor AL3810 synergizes with PD‐1 blockade by reducing CSF1‐driven MHC‐II int tumour‐associated macrophages to optimize TIM‐3 +
Kun Fang, Wen‐Xin Zhang, Zi‐Han Li, Rong Wang, Yi‐Ming Sun, Yi Su, Ying‐Lei Gao, Min Yao, Jian Ding, Yi Chen, Yan‐Fen FangBackground 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‐II int tumour‐associated macrophages, which impaired the function and survival of TCF‐1 − TIM‐3 + CD8 + T‐cells. Meanwhile it preserved MHC‐II high 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.