Najibi Alexander J, Larkin Kerry, Feng Zhaoqianqi, Jeffreys Nicholas, Dacus Mason T, Rustagi Yashika, Hodi F Stephen, Mooney David J
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 USA.
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115 USA.
Cell Mol Bioeng. 2022 Oct 1;15(6):535-551. doi: 10.1007/s12195-022-00742-y. eCollection 2022 Dec.
Tumor 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.
Here, 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 manner . 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.
Together, 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.
The online version contains supplementary material available at 10.1007/s12195-022-00742-y.
肿瘤细胞与免疫细胞通过多种细胞表面蛋白相互作用，这些蛋白既能抑制肿瘤进展，也能促进肿瘤进展。细胞毒性化疗剂量和给药途径对这种相互作用模式的影响仍未完全明确，而这可能有助于开发更有效的癌症联合治疗方法。
在此，我们发现，接触蒽环类药物阿霉素会以剂量依赖的方式改变活的黑色素瘤、乳腺癌和白血病细胞上多种免疫相互作用标志物（主要组织相容性复合体I类分子、程序性死亡受体配体1、程序性死亡受体配体2、信号调节蛋白α、Fas和钙网蛋白）的表达。值得注意的是，中等剂量能最佳诱导免疫原性细胞死亡和免疫激活标志物的表达，而不会使与免疫抑制相关的标志物表达最大化。用中等剂量阿霉素处理过的、表达卵清蛋白的黑色素瘤细胞所接触的骨髓来源树突状细胞被激活，并能最佳地呈递肿瘤抗原。在小鼠黑色素瘤模型中，阿霉素的剂量和给药部位（全身输注与局部给药）均会影响活肿瘤细胞上这些标志物的表达。特别是，从水凝胶中局部释放阿霉素会增加肿瘤细胞上钙网蛋白的表达，而不会诱导免疫抑制标志物，其方式取决于负载剂量。阿霉素处理也会改变患者来源的黑色素瘤细胞中免疫相互作用标志物的表达。
总之，这些结果说明了标准护理化疗以不同方式给药时，如何导致癌细胞上免疫原性标志物的不同表达。这些发现可能为癌症化疗免疫疗法联合治疗的开发提供信息。
网络版包含可在10.1007/s12195-022-00742-y获取的补充材料。
