Biomaterial-based Radio-immunotherapy For Cancer

Cancer,which killing～10 million people every year,has become the second leading cause of death after cardiovascular and cerebrovascular diseases.Meanwhile,as the incidence of cancer increases,the global burden of cancer will further increase.Nowadays,the treatment strategies for cancer mainly include surgery,radiotherapy,chemotherapy,targeted therapy,etc,the main goal of which is to completely cure cancer or effectively prolong the life of patients.With lots of advantages,such as radiotracer,accurate quantification,wide application range,non-invasive treatment,positive anti-tumor biological effects,etc,radiotherapy can kill tumor cells effectively with high-energy ionizing radiation.However,it also has some limitations,such as the inability of radiotherapy to metastatic and recurrent tumors,radiation resistance caused by tumor hypoxia,and the side effects of radiotherapy on normal tissues,etc.How to improve and solve these difficulties is the current problem facing radiotherapy.In recent years,immunotherapy as a new and most promising tumor treatment strategy has attracted widespread attention,which can activate the body’s own immune system to fight against tumors.At present,tumor immunotherapy mainly includes immune checkpoint therapy,adoptive cell immunotherapy and cancer vaccine.Among them,immune checkpoint blocking therapy is widely used in clinical treatment,however,the response rate of which is only 20%～30%.At the same time,due to the heterogeneity,complexity and diversity of tumors,the current cancer treatment strategy tends to be combined therapy.In addition to killing tumor cells directly,radiotherapy can also promote the release of tumor-specific antigens and increase the chance for immune cells to recognize cancer cells.Therefore,combining radiotherapy with immunotherapy may be an effective treatment strategy.In addition,with the rapid development of biotechnology and nanomedicine,various functional biomaterials have shown great potential in the basic research field of tumor therapy.Such biomaterials can not only improve the treatment efficiency with low side effects but also have special effects such as immune stimulation.Therefore,combining radiotherapy and immunotherapy with the assistance of biomaterials may be more effective in cancer treatment.Based on the above background,in this doctoral dissertation,from different perspectives of the limitations of radiotherapy,we are committed to designing and developing a series of radionuclide labeled biomaterials combined with immunotherapy,and systematically studying their contributions to improve the efficacy of internal radioisotope therapy,immune stimulation effect and tumor mcroenvironment(TME)regulation.Subsequently,we demonstrate the feasibility of biomaterial-based tumor radio-immunotherapy strategies in multiple tumor models and further explored the mechanism.The main research findings of this paper are summarized as follows:Chapter 1:The progress and challenges of radiotherapy and immunotherapy for cancer in recent years are briefly reviewed firstly and the topic basis and research content of this paper are then emphasized.Chapter 2:Due to the complexity,heterogeneity and metastasis of tumors,combination therapy is frequently put into use in clinical cancer therapy.Herein,we design radionuclide-labeled gold nanoclusters(99mTc@Au NCs and 177Lu@Au NCs),which can not only induce dendritic cell(DC)maturation and improve anti-tumor immune response,but also up-regulate the expression of PD-L1 in distal tumors while effectively enhancing radioisotope internal radiotherapy.When combined with immune checkpoint inhibitor(αPD-L1),177Lu@Au NCs can effectively clear the primary tumor and inhibit the growth of the distal tumors.Especially in transgenic mice with spontaneous metastasis of breast cancer,our strategy can significantly inhibit the growth of metastatic tumors and prolong the survival of mice.Chapter 3:Oxygen plays an important role in cancer therapy.Tumor hypoxia microenvironment can not only lead to radiation resistance,but also form an immunosuppressive microenvironment.Therefore,we design a nano-oxygen generator(APPs-PEG)based on a metal-organic framework,which can not only stably label 177Lu,but also efficiently catalyze the decomposition of H2O2 at the tumor site to produce oxygen,thus eliminating the limitation of oxygen dependence of internal radiotherapy.In addition,increased oxygen in the TME can promote the infiltration of cytotoxic T cells(CTLs)and affect the glucose metabolism of tumor cells,further reducing the proliferation activity of tumor cells,and greatly inhibiting the distal tumor growth and reducing the formation of metastatic lesions.Chapter 4:In addition to synthetic biomaterials,bacterial vectors with a natural immune-stimulatory effect can induce both innate and adaptive immunity.Herein,we design inactivated bacteria labeled with radioactive iodine(125I/131I)in combination with aPD-L1 to achieve high-efficiency radio-immunotherapy for tumors.We find that 131I labeled bacterial vector can not only effectively kill the tumor in situ,on the one hand,the released tumor antigen and bacterial vector can effectively promote the cross presentation of DCs and activate the anti-tumor immune response.On the other hand,the release of tumor exosomes after internal radiotherapy can also up-regulate the expression of remote tumor PD-L1 and enhance the immunotherapy effect of aPDL1.At the same time,DNA fragments from bacteria and tumour cells can further activate the cGAS-STING pathway,which enables the assistance of innate immunity for cancer immunotherapy.Therefore,we explore the role and mechanism of radiolabeled bacterial vector in tumor radio-immunotherapy,providing a new idea for the combination of bacteria and radiotherapy,and the synergistic anti-tumor of innate immunity and adaptive immunity.In conclusion,a series of radiolabeled biomaterials developed by us on the one hand can effectively improve the therapeutic effect of internal radiotherapy;on the other hand,the immune stimulation or TME regulation function of radiolabeled biomaterials can also improve the anti-tumor immune response of the body.After combining with immune checkpoint inhibitors,the growth of distal tumors and metastatic tumors can be effectively inhibited,and the survival of mice can be prolonged.Series studies of us not only provide a new strategy to solve the limitations of traditional internal radiotherapy,but also provide a new idea for combining tumor radiotherapy and immunotherapy.