Compound Liposomal Targeting-drug Delivery Of Irinotecan/JQ1 And Its Application For Colorectal Cancer Immunotherapy

Tumor immunotherapy,as an innovation of tumor therapy,has advantages of wide application for various tumor types,and durable treatment outcomes,with substantial extension of survival time of cancer patients.As a case in point,the PD-1 immune checkpoint inhibitors have been widely used in cancer therapy,especially for immunogenic cancers,such as melanoma,lung cancer,kidney cancer and currently also used to classical Hodgkin's lymphoma,urothelial cancer and colorectal cancer with microsatellite instability-high(MSI-H)or mismatch repair deficiency(dMMR).Although the colorectal cancer patients with MSI-H or dMMR show more notable and durable treatment response rate,there are only 5%of metastatic CRC patients bearing dMMR or MSI-H tumors.In general,combination therapy takes better outcomes,compared with monotherapy.Therefore,the combination of various cancer therapies is clinically used to enhance the anti-tumor effects,for example,the combination of chemotherapy and immunotherapy.It has been well acknowledged that some chemotherapeutics can induce an immunogenic cell death.The immunogenic cell death can trigger the anti-tumor immune response and thus yield the synergistic effect of chemo-and immunotherapy.For instance,irinotecan,a first-line drug for advanced colon cancer,has a function of inducing inmmunogenic cell death and eliciting anti-tumor immunity.This research focued on the anticancer treatment via a mechanism of immunogenic cell death by using irinotecan and an immune checkpoint inhibitor JQ1 for combination therapy.Irinotecan played a dual role of chemotherapy and induction of immunogenic cell death,and the antitumor immunity was further boosted by JQ1.This study developed a tumor-targeting delivery liposomal system(termd APCJ),of which the liposome surface was modified by anti-PD-L1 with co-encapsulation of irinotecan and JQ1.The results showed that APCJ was with regular sphere with a uniform size distribution of around 160 nm and with a good colloidal stability.Studies in vitro showed that the APCJ displayed a significantly increased uptake efficiency in the tumor cells.The combo drugs promoted the maturation of dendritic cells(DC)in the tumor cells/DC co-culture system,and the result was obvious in the APCJ treatment group.In addition,the DC treated by the APCJ can enhance the IFN-?secreted by the T cells.It suggested that APCJ promoted antitumor immunity via a possible mechanism of promoting DC maturation and activating T cells.In the CT26 subcutaneous tumor-bearing mice,the APCJ treatment group showed the best therapeutic efficiency with remarkable prolonged survival time among all of the treatment groups.It further demonstrated that APCJ treatment enhanced the matured DC in the lymph nodes and spleen,increased the IFN-?~+CD8~+T cell intratumor infiltration and the secretion of IFN-?,but suppressed the PD-L1 and reduced the number of CD4~+Foxp3~+regulatory T cells.It indicated that APCJ can elicit antitumor immunity for inhibition of tumor growth.In conclusion,this study showed the combination of irinotecan and JQ1 can yield antitumor immunity for colorectal tumor treatment.The anti-PD-L1 antibody-modified liposome for codelivery was developed for enhancing tumor-targeting efficiency.With the treatment of APCJ,the antitumor immune responses were elicited and the PD-L1down-regulated,thus promoting the nomoralization of antitumor immunity for suppressing tumor growth.