Regulation Of IRE1α/XBP1 Signaling Of Macrophage In The Microenvironment Of Colorectal Cancer

Immune microenvironment plays an important role in the multistep process of colorectal cancer from carcinogenesis to treatment.Currently,improvements in traditional immunotherapy for colorectal cancer patients in clinic are slowing down.Tumor microenvironment is composed of tumor cells,endothelial cells,fibroblasts,immune cells,macrophage,in addition to the cytokines,matrix metalloproteinases(MMPs),and extracellular matrix(ECM)they produce.Tumor microenvironment not only plays an important role in tumor progression and metastasis,but also has profound effects on therapeutic efficacy.Macrophages are one of the most abundant immune groups in intestine and contribute to tumor development and treatment.Macrophages in tumor microenvironment could be "educated" to be tumor-promoting.So,targeting Tumor-associated macrophage(TAM)could improve therapeutic efficacy.Abnormal accumulation of unfolded proteins in this compartment causes a state of“ER stress,”which is a hallmark feature of secretory cells and many diseases,including diabetes and cancer.Adaptation to protein-folding stress is mediated by activation of a most conserved UPR arm which is IRE la.During ER stress,this kinase uses its endoribonuclease activity to excise a 26-nucleotide fragment from the unspliced Xbpl mRNA.Colorectal cancer subverts the normal activity of infiltrating macrophages to inhibit the function of otherwise protective anti-tumor macrophages.Eliminating or "re-programming" TAMs can abrogate CRC progression,but the precise molecular pathways that tumors exploit in macrophages to co-opt their activity remain poorly understood.Here,we uncover an unexpected role for the ER stress response factor XBP1 as a crucial driver of macrophage repolarization with anti-tumoral effects in CRC.Our results showed that robust XBP1 activation was found in TAM,infiltrated in tumor microenvironment of colorectal cancer patients and AOM-DSS mice.XBP1 activation would drive colorectal cancer progression and metastasis.While TAM-specific XBP1 deletion restored their immunostimulation activity and inhibited the tumor growth by downregulation of IL-6,VEGF and IL-4.Moreover,selective XBP1 silencing in macrophages inhibited the expression of SIRPA and THBS1,and reduced the autologous recognition of macrophages to tumor cells.Thus,XBP1 deletion alters the macrophage from immune-suppressive to immune-promoting.Removing macrophages and SIRPA antibody treatment in AOM-DSS mice had certain therapeutic effect,but the effect was not as effective as inhibiting the activation of XBP1 by 4u8C or knockout XBP1 in macrophages.The results of clinical outcome data in two GEO database showed that the high expression of TAM markers CD 163 and CD206 is correlated with poor survival in cancer patients.More importantly,high expression of XBP1 target genes,such as SIRPA and VEGF in human tumors is significantly correlated with shorter survival of cancer patients.In summary,we investigated the role of IRE1а/XBP1 pathway on development of colorectal cancer and clarify the regulatory mechanisms of IRE1а/XBP1 signal pathway in tumor microenvironment.By targeting XBP1,we have switched the function of macrophage from tumor-promoting to tumor-suppressing,and explored its application in colorectal cancer.Our result elucidated the regulatory mechanism of the endoplasmic reticulum stress response in macrophages and the potential of the IRE1а/XBP1 signaling pathway as a therapeutic target for colorectal cancer.