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Dose-dependent efficacy of CX1003 in NSCLC immunotherapy: High dose for T cell response, low dose for apoptosis
Yanxia Liu1, Xiaomi Li1, Baolan Li1
1Medical Oncology, Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China; Joint Laboratory for Precision Diagnosis and Treatment Translational Research in Malignant Tumors, Gynecologic Oncology Basic and Clinical Research Laboratory, Capital Medical University, Beijing, China.
Background:
Immunotherapy targeting programmed cell death protein (death-ligand) 1 [PD-(L)1] have improved the survival of patients with non-small cell lung cancer (NSCLC), however, the subset of the population that responded remains limited. Combination therapy may broaden the benefit population and receptor tyrosine kinase inhibitor (RTKI) provides a promising approach. Previous research has demonstrated that RTKI can enhance the efficacy of immunotherapy in a dose-dependent manner. Here, we investigated the synergistic effects of different doses CX1003, a novel RTKI, and PD-L1 blockade in NSCLC using a mouse model with subcutaneous tumor.
Methods:
The synergistic treatment response of CX1003 and PD-L1 blockade was evaluated in subcutaneous in NSCLC mouse models. To elucidate the underlying mechanisms, various techniques including immunofluorescence, spectral flow cytometry, transcriptomics were employed to analyze the tumor microenvironment.
Results:
Both doses of CX1003 enhanced the efficacy of PD-L1 blockade, with the high-dose combination therapy exhibiting superior antitumor efficacy in subcutaneous tumors. Subsequent analysis of the tumor microenvironment(TME) indicated that both doses of CX1003 induced tumor vascular normalization, but only high-dose CX1003 promoted CD8 + T lymphocyte infiltration and cytotoxicity when combined with PD-L1 blockade, suggesting that different doses of CX1003 combined with immunotherapy may have different mechanisms. The transcriptional landscape revealed enhancement of cell death related signaling following low-dose CX1003 and immune signaling following high-dose CX1003 when combined with PD-L1 blockade. Subsequent experiments indicated that low-dose CX1003 triggered apoptosis through the mitochondrial pathway, and high-dose CX1003 enhanced TCR signaling and IL-2 secretion when combined with PD-L1 blockade. Moreover, IL-2 and MAP2K2, the genes upregulated in the TCR signaling pathway following high-dose CX1003 combined with PD-L1 blockade treatment, are correlated with the prognosis of NSCLC receiving immunotherapy.
Conclusions:
Both high and low doses of CX1003 enhance the efficacy of PD-L1 blockade in NSCLC, albeit through distinct mechanisms. High-dose CX1003 enhance the efficacy via inducing the T cell-mediated immune response, whereas low dose augment efficacy by promoting apoptosis. These findings provide rationale for treating NSCLC patients with the combination therapy.
