肿瘤微环境的免疫成分对癌症生物过程有决定性的影响，因此具有深刻的临床意义。本研究中，我们分析了积分素β4（ITGB4）和内皮细胞中E-/P-选择素在肿瘤基质内的协同效应，通过塑造局部和全身免疫环境来调节肿瘤生长。我们使用了几种不同实体人类癌症类型的预临床小鼠模型（异种移植和同基因），通过组织学和生物化学方法，以及3D体外实验，确定了ITGB4（通过shRNA介导的肿瘤细胞的下调）和E- / P-选择素（在小鼠中进行敲除）对于肿瘤生长的影响；测量了对凋亡、增殖和肿瘤内信号通路的影响；通过流式细胞术和免疫组织化学确定了肿瘤内和全身免疫细胞组成的变化；通过ELISA和3D入侵实验测量了趋化因子的水平和其吸引潜力。我们观察到ITGB4和E- / P-选择素之间的协同效应对于调节肿瘤生长非常强大，伴随着CD11b + Gr-1Hi细胞（即，来自髓样细胞的抑制性细胞，MDSCs）的招募增加到ITGB4-depleted的肿瘤中。ITGB4-depleted的肿瘤经历细胞凋亡，并通过增加不同趋化因子的分泌，积极地吸引MDSC，后者已知在多种癌症中促进肿瘤生长。MDSC进入肿瘤在关键地依赖E- / P-选择素的表达。对临床样本的分析证实了肿瘤中ITGB4表达和肿瘤浸润的白细胞数之间的负相关关系。这些发现表明，ITGB4Lo 肿瘤在MDSC定向免疫疗法中具有明显的易感性。©2023. 作者。

The immunological composition of the tumor microenvironment has a decisive influence on the biological course of cancer and is therefore of profound clinical relevance. In this study, we analyzed the cooperative effects of integrin β4 (ITGB4) on tumor cells and E-/P-selectin on endothelial cells within the tumor stroma for regulating tumor growth by shaping the local and systemic immune environment.We used several preclinical mouse models for different solid human cancer types (xenograft and syngeneic) to explore the role of ITGB4 (shRNA-mediated knockdown in tumor cells) and E-/P-selectins (knockout in mice) for tumor growth; effects on apoptosis, proliferation and intratumoral signaling pathways were determined by histological and biochemical methods and 3D in vitro experiments; changes in the intratumoral and systemic immune cell composition were determined by flow cytometry and immunohistochemistry; chemokine levels and their attracting potential were measured by ELISA and 3D invasion assays.We observed a very robust synergism between ITGB4 and E-/P-selectin for the regulation of tumor growth, accompanied by an increased recruitment of CD11b+ Gr-1Hi cells with low granularity (i.e., myeloid-derived suppressor cells, MDSCs) specifically into ITGB4-depleted tumors. ITGB4-depleted tumors undergo apoptosis and actively attract MDSCs, well-known to promote tumor growth in several cancers, via increased secretion of different chemokines. MDSC trafficking into tumors crucially depends on E-/P-selectin expression. Analyses of clinical samples confirmed an inverse relationship between ITGB4 expression in tumors and number of tumor-infiltrating leukocytes.These findings suggest a distinct vulnerability of ITGB4Lo tumors for MDSC-directed immunotherapies.© 2023. The Author(s).