Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, 75080, USA.
Department of Biomedical Engineering, UT Southwestern Medical Center, Dallas, TX, 75235, USA.
Sci Rep. 2024 Jun 19;14(1):14142. doi: 10.1038/s41598-024-64780-4.
Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both "separated" and "contact" scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.
癌细胞从血液中招募中性粒细胞进入肿瘤组织，这些免疫细胞促进了许多实体肿瘤的进展。小鼠研究表明，通过抑制中性粒细胞趋化因子受体 CXCR2 来阻止中性粒细胞向肿瘤的募集，可能成为胰腺癌的一种潜在免疫疗法。然而，中性粒细胞在人类中促进肿瘤进展的机制，以及 CXCR2 抑制如何可能作为癌症治疗，仍然难以捉摸。在这项研究中，我们开发了一种基于人源细胞的微生理系统，以量化中性粒细胞-肿瘤球体在“分离”和“接触”两种情况下的相互作用。我们发现，中性粒细胞通过分泌可溶性因子和与癌细胞直接接触来促进肿瘤球体的侵袭。然而，它们仅通过直接接触促进肿瘤球体的增殖。有趣的是，用 CXCR2 抑制剂 AZD-5069 处理可通过阻断与中性粒细胞的直接接触来减弱肿瘤球体的侵袭和增殖。我们的研究结果还表明，CXCR2 抑制可减少中性粒细胞向肿瘤球体的迁移。这些发现为人类中性粒细胞的促肿瘤机制以及 CXCR2 抑制在胰腺癌中的肿瘤抑制机制提供了新的见解，并可能有助于基于中性粒细胞的新型免疫治疗策略的设计和优化。
