Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells.
Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells.
复制标题
化疗剂量影响癌细胞上免疫相互作用标记物的表达。
DOI：
10.1007/s12195-022-00742-y
复制
发表时间：
2022
影响因子：
2.8
通讯作者：
Mooney,DavidJ
中科院分区：
文献类型：
--
作者：
Najibi,AlexanderJ;Larkin,Kerry;Feng,Zhaoqianqi;Jeffreys,Nicholas;Dacus,MasonT;Rustagi,Yashika;Hodi,FStephen;Mooney,DavidJ
简介肿瘤和免疫细胞通过多种细胞表面蛋白相互作用，这些蛋白可以抑制或促进肿瘤进展。细胞毒性化疗剂量和给药途径对这种相互作用的影响尚不完全清楚，并且可以支持开发更有效的癌症治疗联合疗法。方法和结果在这里，我们发现暴露于蒽环类阿霉素会改变活黑色素瘤、乳腺癌和白血病细胞中多种免疫相互作用标志物（MHC-I、PD-L1、PD-L2、CD47、Fas 和钙网蛋白）的表达。体外剂量依赖性方式。值得注意的是，中间剂量最好地诱导免疫原性细胞死亡和免疫激活标记物的表达，而不会最大化与免疫抑制相关的标记物的表达。暴露于表达卵清蛋白的黑色素瘤的骨髓源性树突状细胞经中等阿霉素剂量处理后被激活并最好地呈递肿瘤抗原。在小鼠黑色素瘤模型中，阿霉素剂量和递送位置（全身输注与局部给药）都会影响活肿瘤细胞上这些标记物的表达。特别是，阿霉素从水凝胶中的局部释放增加了肿瘤细胞上钙网蛋白的表达，而不诱导免疫抑制标记物，其方式取决于加载剂量。阿霉素暴露还改变了患者来源的黑色素瘤细胞中免疫相互作用标记物的表达。结论总的来说，这些结果说明了标准护理化疗在以各种方式施用时如何导致癌细胞上免疫原性标记物的独特表达。这些发现可能为癌症治疗的化学免疫疗法组合的开发提供信息。
IntroductionTumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment.Methods and ResultsHere, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent mannerin vitro. Notably, an intermediate dose best induced immunogenic cell death and the expression of immune-activating markers without maximizing expression of markers associated with immune suppression. Bone marrow-derived dendritic cells exposed to ovalbumin-expressing melanoma treated with intermediate doxorubicin dose became activated and best presented tumor antigen. In a murine melanoma model, both the doxorubicin dose and delivery location (systemic infusion versus local administration) affected the expression of these markers on live tumor cells. Particularly, local release of doxorubicin from a hydrogel increased calreticulin expression on tumor cells without inducing immune-suppressive markers, in a manner dependent on the loaded dose. Doxorubicin exposure also altered the expression of immune-interacting markers in patient-derived melanoma cells.ConclusionsTogether, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment.