Regulation Of The Functional And Activity Of T-cells For Cancer Theranostics

The efficacy of immune activation related cancer therapy greatly relies on the performance of tumor-infiltrating T cells which play a central role in recognizing and killing cancer cells.Immunotherapy based on regulating T-cell activity has achieved promising results.However,the broad effectiveness of T cell-based cancer therapy in the clinic is still elusive.One major reason is that the immunosuppressive tumor microenvironment(TME)may pose great challenge to T cells in terms of the survival,proliferation and cytotoxic activity when they reach the tumor region.These observations are parts of the ubiquitous occurrence of the "T-cell exhaustion" caused by multiple mechanisms,which further urge the needs to realize the in situ activity of T cells in the TME during cancer immunotherapy.Due to the importance of the TME in regulating T-cell responses,we investigated the effects of biological,physical,and/or chemical processes in TME in regulating T-cell activity,taking the advantages of materials science and nanotechnology in tumor theranostics.This study centers the in situ activity of T cells in the tumor for cancer theranostics by direct or indirect regulatory strategies which may shed new light on improving the efficacy of engineered immune cells for cancer treatment.The main content is summarized as follows:In chapter 1,we reviewed the current status of cancer immunotherapy and current strategies of reinvigorating T-cell activity,with an emphasis on the principles,advantages,and the challenges for the development of various therapeutic strategies.Meanwhile,we further summarized biological factors(e.g.,macrophages,dendritic cells,tumor associated fibroblasts,neutrophils and NK cells),physical factors(e.g.,temperature and the matrix hardness)and chemical factors(e.g.,pH value,electronic respiratory chain transfer,oxygen concentration,and REDOX state)regarding to their impact on T-cell activity.According to the necessary conditions for T-cell activation,we proposed to develop new strategies form the biological,physical and chemical environment factors o to regulate the T-cell activity in situ.This thesis is expected to shed new light on regulating the T-cell activity for cancer treatment.In chapter 2,from a biological perspective,we designed tumor-associated macrophage targeted PLGA nanoparticles that exploit low-dose reactive oxygen species(ROS)produced by the Cherenkov effect to reprogram tumor-associated M2 macrophages into M1 macrophages.This strategy can effectively enhance the tumor antigen presentation process and the T-cell activity,thereby inhibiting tumor growth and metastasis.This work utilized the interaction between stromal cells in the TME to realize the regulation of T-cell activity in the tumors,which provided a new way for subsequent research based on the regulation of T-cell activity.In chapter 3,from a physical perspective,this work presented the use of externally applied graphene film(GF)to regulate the activity of T cells through the eminent resonant thermal radiation effect.In a murine CT-26 syngeneic tumor model,GF itself elicited an enhanced T-cell-based immune response and more importantly,served as an externally applied ’adjuvant’ to T-cell activity in aPD-L1 combination immunotherapy for improved rates of tumor depletion and inhibition of tumor recurrence.This work centered the unmet needs of regulating the activity of intratumoral T cells in situ,in which the use of GF with little systemic safety concern and the high efficiency may promise to translation of cancer immunotherapy in the future.In chapter 4,from a chemical perspective,we designed T-cell-targeted fusogenic liposomes(T-Fulips)to simultaneously regulate and quantify the activity of T cells by exploiting the surface redox status of T cells as a vivid chemical target.The T-Fulips equipped with 2,2,6,6-tetramethylpiperidine(TEMP)groups could serve as reactive oxygen species(ROS)’decoys’ harboring T cells from oxidation-induced loss of activity.Meanwhile,the production of paramagnetic TEMPO radicals provided prominent changes of proton T1 relaxation time in a "0 to 1" manner for magnetic resonance imaging(MRI)quantification of the activity of T cells.This study centers the in situ activity of T cells for cancer theranostics by a chemical targeting strategy which may shed new light on engineering T cells for cancer treatment.