XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer.
XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer.
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XBP1 调节人结直肠癌中肿瘤相关巨噬细胞的促肿瘤功能
DOI：
10.1038/s41392-021-00761-7
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发表时间：
2021-10-20
影响因子：
39.3
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Zhao Y;Zhang W;Huo M;Wang P;Liu X;Wang Y;Li Y;Zhou Z;Xu N;Zhu H
巨噬细胞是结直肠癌（CRC）中最丰富的免疫细胞之一。重新培养肿瘤相关巨噬细胞（tam）从原肿瘤活性转变为抗肿瘤活性是一种有吸引力的治疗策略，值得进一步研究。然而，人们对tam中激活的关键途径知之甚少。本研究对CRC中浸润的CD206+ tam进行了分类，并进行了RNA-seq分析。差异表达基因在未折叠蛋白反应/内质网应激反应过程中富集，并且在tam中特异性观察到XBP1剪接/激活。TAMs中XBP1的激活促进了CRC的生长和转移。XBP1的消融抑制了tam中促肿瘤细胞因子的表达，包括IL-6、VEGFA和IL-4。同时，XBP1缺失可直接抑制SIRPα和THBS1的表达，从而阻断“不要吃我”的识别信号，增强吞噬作用。使用AAV2-sgXBP1编辑治疗性XBP1基因增强了抗肿瘤活性。总之，XBP1在tam中的激活通过提高促肿瘤细胞因子的表达和分泌以及抑制巨噬细胞吞噬来驱动CRC的进展。靶向TAMs中的XBP1信号可能是CRC治疗的潜在策略。
Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206+TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking “don’t eat me” recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.
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影响因子：
5.2
作者：
Augustin RC;Delgoffe GM;Najjar YG
通讯作者：
Najjar YG
影响因子：
30.5
作者：
Bettigole SE;Lis R;Adoro S;Lee AH;Spencer LA;Weller PF;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Silberman PC;Rutkowski MR;Chopra S;Perales-Puchalt A;Song M;Zhang S;Bettigole SE;Gupta D;Holcomb K;Ellenson LH;Caputo T;Lee AH;Conejo-Garcia JR;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
7.4
作者：
Chen C;Zhang X
通讯作者：
Zhang X
影响因子：
15.3
作者：
Iwakoshi, Neal N.;Pypaert, Marc;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.