The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile ...The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile and regulatory mechanism of Sirpαexpression in tumor-associated macrophages(TAMs)are still not clear.Here,we found that the expression of Sirpαin TAMs increased dynamically with colorectal cancer(CRC)progression.Mechanistically,CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2αfrom the cytoplasm in TAMs.Ap-2αfunctioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at−1396/−1391 in the mouse Elk-1 promoter.Subsequently,the Elk-1 protein bound to two conserved sites,CTTCCTACA(located at−229/−221)and CTTCCTCTC(located at−190/−182),in the mouse Sirpαpromoter and promoted Sirpαexpression in TAMs.Functionally,the macrophage-specific knockout of Ap-2αnotably promoted the phagocytic activity of TAMs and suppressed CRC progression,whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1,which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner.Furthermore,we showed that Elk-1 expression was positively correlated with Sirpαexpression in TAMs and was associated with poor survival in CRC patients.Taken together,our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.展开更多
基金supported in part by award numbers 81972775(S.Y.),81602628(X.L.)from the National Natural Science Foundation of ChinaSWH2017YQPY-01(S.Y.)and SWH2016ZDCX1002(H.L.)from Southwest Hospital Research and 2018ZDXM016(S.Y.)from the Chongqing Science and Health Joint Fund.
文摘The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile and regulatory mechanism of Sirpαexpression in tumor-associated macrophages(TAMs)are still not clear.Here,we found that the expression of Sirpαin TAMs increased dynamically with colorectal cancer(CRC)progression.Mechanistically,CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2αfrom the cytoplasm in TAMs.Ap-2αfunctioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at−1396/−1391 in the mouse Elk-1 promoter.Subsequently,the Elk-1 protein bound to two conserved sites,CTTCCTACA(located at−229/−221)and CTTCCTCTC(located at−190/−182),in the mouse Sirpαpromoter and promoted Sirpαexpression in TAMs.Functionally,the macrophage-specific knockout of Ap-2αnotably promoted the phagocytic activity of TAMs and suppressed CRC progression,whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1,which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner.Furthermore,we showed that Elk-1 expression was positively correlated with Sirpαexpression in TAMs and was associated with poor survival in CRC patients.Taken together,our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.
