Abstract

Graphical abstract

Keywords

Abbreviations

۱٫ Introduction

۲٫ Materials and methods

۳٫ Results

۴٫ Discussion

۵٫ Conclusions

Author contributions

Declaration of Competing Interest

Acknowledgments

Appendix A. Supplementary data

References

Abstract

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

۱٫ Introduction

As the third leading cause of cancer-related deaths worldwide (e.g., 881,000 deaths estimated in 2018)1, colorectal cancer (CRC, a cancer of the colon or rectum) is an obvious disease burden requiring effective, safe and widely-applicable treatments. Recent research in cancer immunology has led to the development of different immunotherapeutic strategies2, 3, 4. Among these, strategies that exert the blockade of immune checkpoint pathways [e.g., cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-L1)] have achieved favorable outcomes in a range of solid tumors5. However, it has been reported that only a minority of patients (up to 15% of the CRC population), who are identified with mismatch repair (MMR)-deficient CRC, respond positively to immune checkpoint blockade therapy6, while the response rate remains low in MMR-proficient CRC patients7. This failure is strongly attributed to the immunosuppressive feature of the tumor microenvironment (TME)8. Therefore, approaches designed to reprogram the TME may improve the therapeutic efficacy of immune checkpoint inhibitors9, potentially providing therapeutic benefit for the wide spectrum of CRC patients.

Immunogenic cell death (ICD) is characterized as immunogenic apoptosis that activates damage-associated molecular patterns (DAMPs) in dying or dead tumor cells in response to certain stimuli10. DAMPs as danger signals activate dendritic cells (DCs) for the presentation of tumor-associated antigens (TAAs), which subsequently induce T cell-mediated immunological responses against living tumor cells of the same kind10. The concept of ICD has revolutionized the traditional view of chemotherapeutic agents that are considered cytotoxic and poorly immunogenic. For example, chemotherapeutic drugs such as anthracyclines11, oxaliplatin12, bortezomib13 and cardiac glycosides14 have been identified as the putative ICD inducers. Recently, evaluation of chemotherapeutics as potential ICD inducers has gained increasing attention. In addition, ICD is often concomitant with the production of reactive oxygen species (ROS)10, and the efficacy of ICD may be enhanced by ROS-inducing strategies15, 16, 17. Therefore, it is hypothesized that a combination of ICD- and ROS-inducing strategies will mediate the remodeling of immunosuppressive TME and achieve synergistic immunotherapeutic efficacy with immune checkpoint blockade.