2. Academic Validation
  3. Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance

  • J Adv Res. 2024 Aug 19:S2090-1232(24)00366-7. doi: 10.1016/j.jare.2024.08.023.
Xiaoqing Sun 1,  Caiqin Wang 2,  Jianghua Cao 3,  Jing Li 3,  Gang Ma 1,  Xianqiu Wu 4,  Peng Sun 3,  Yu Wang 3,  Jiajia Huang 5,  Robert Peter Gale 6,  Zhiming Li 7
Affiliations

Affiliations

  • 1 Department of Intensive Care Medicine (ICU), State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R.China.
  • 2 Department of Lymphoma and Hematology, the Afliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha 410013, Hunan, P.R.China.
  • 3 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R.China.
  • 4 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
  • 5 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R.China. Electronic address: huangjiaj@sysucc.org.cn.
  • 6 Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.
  • 7 Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R.China. Electronic address: lizhm@sysucc.org.cn.
PMID: 39168245 DOI: 10.1016/j.jare.2024.08.023
Abstract

Introduction: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature.

Objectives: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL.

Methods: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using Antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA Sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 Inhibitor, could reverse ibrutinib resistance through CCK-8 and Caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line.

Results: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell Apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone.

Conclusion: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 Inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

Keywords

BTK inhibitor; CXCL5; CXCR2; Macrophages; Mantle cell lymphoma; Resistance.

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