B‑cell lymphoma is difficult to cure because of its biological and clinical heterogeneity, and due to native chemoresistance. Immunotherapies that overcome cancer‑induced immune evasion have been the center of recent developments in oncology. This is emphasized by the accomplishment of various agents that disrupt programmed cell death protein 1 (PD‑1)‑mediated immune suppression in diverse tumors. However, while PD‑1 blockade has been effective in numerous malignancies, a significant proportion of cancers, including B‑cell lymphoma, show certain rates of primary resistance to these therapeutic strategies. Histone deacetylase inhibitors (HDACis) have exhibited anticancer activity though suppressing cell proliferation, inducing differentiation and triggering apoptosis. The present study aimed to explore a therapeutic strategy combining a HDACi (romidepsin) and PD‑1 blockade (BMS‑1) in B‑cell lymphoma, utilizing a constructed mouse model of B‑cell lymphoma. The IC50 of the two inhibitors was confirmed by MTT assay, and their inhibitory effects were revealed to be dose‑ and time‑dependent. The data demonstrated that the combined treatment of romidepsin and BMS‑1 synergistically inhibited the growth of B‑cell lymphoma. Furthermore, it was revealed that romidepsin and BMS‑1 synergistically triggered apoptosis in mouse B‑cell lymphoma. The synergistic effect of these agents was capable of activating tumor‑infiltrating lymphocytes, particularly CD3+CD4+ and CD3+CD8+ T cells. The results of the present study underscore the potential of HDAC inhibition in conjunction with PD‑1 blockade as a novel therapeutic approach for B‑cell lymphoma, highlighting the synergistic effects of these two mechanisms in enhancing antitumor immunity.
Rui Zhang,Ge Cheng,Shengnan Liu,Hongying Lv,Juan Li
Designing a multi-target nanomedicine without a carrier is pivotal for successful cancer nanotherapy. This study details a novel four-in-one RRX/BMS/CA4/PTX nanomedicine by simple nanoprecipitation. In this multi-target pure nanomedicine, paclitaxel (PTX) causes the immunogenic cell death of 4T1 tumour cells and the differentiation of marrow-derived suppressor cells (MDSCs) into dendritic cells (DCs) at low dose; repertaxin (RRX) selectively depletes cancer stem cells (CSCs) that are not killed by paclitaxel to inhibit lung metastasis from the breast; BMS-1 blocks the PD-1/PD-L1 pathway for proliferating effector T cells; and combretastatin A4 (CA4) targets tumour microvessels to cut off the blood supply in the tumour microenvironment. The synergy of multi-target therapies results in excellent antitumour effects. The tumour inhibition rate of 4T1 tumours is 92.5%, and the lung metastasis suppression rate exceeds 90%; no relapse is observed at 46 days after the treatment endpoint, and the survival of 50% of mice is prolonged by 95 days. Due to the low dose of PTX administration, the systemic toxicity of the RRX/BMS/CA4/PTX nanomedicine is not found. Our results suggest a strategy for designing multi-target pure nanomedicines with simple construction and efficacious therapeutic responses that present potential for clinical transformation.
Jie Yu,Xidong He,Zigui Wang,Yupeng Wang,Sha Liu,Xiaoyuan Li,Yubin Huang
Immune checkpoint blockade (ICB) therapy in combination with immunogenic death (ICD) triggered by photothermal therapy (PTT) and oxaliplatin (OXA) treatment was expected to elicit both innate and adaptive immune responses for tumor control and metastasis prevention. In this study, a photothermal agent (IR780), a folic acid (FA) linked oxaliplatin (OXA) prodrug, and PD-L1 inhibitors (BMS-1) were integrated into a liposomal system. The FA tumor-targeting and enhanced permeability and retention (EPR) effect of the liposomal system prolonged circulating times and increased accumulation in tumors, resulting in an enhanced photothermal effect and less systemic toxicity. In addition, PTT and OXA had a considerable synergistic effect in the induction of a combined ICD. The PD-1/PD-L1 checkpoint, which is a negative immune regulatory mechanism, could be blocked by the thermosensitive released BMS-1. Finally, ICD was harnessed to synergize with a small molecule PD-L1 inhibitor for activation of the immune system in the treatment of tumor relapse and metastasis.
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