A nanoplatform to boost multi-phases of cancer-immunity-cycle for enhancing immunotherapy
Graphical abstract
The schematic diagram of Mn/CaCO3@PL/SLC NPs, which augments the all-immunity-cycle by inducing immunogenic cell death of tumor cells, polarizing the immunosuppresive tumor microenvironment and increasing the vitality of tumor-infiltrating T lymphocytes.
Introduction
Immunotherapy has received tremendous attention owing to unique advantages, but still suffers unsatisfactory outcomes in clinic. [1,2] Effective immune response in anti-tumor treatment reflects a range of carefully regulated events that is known as cancer-immunity cycle. [3] The continuous multi-link processes include tumor-associated antigens (TAAs) release and presentation, T cells activation and infiltration, as well as tumor cells destruction. [3,4] Failure of any phase would lead to poor immune response. [5] Therefore, it is meaningful to develop a nanoplatform that can tailor all these phases.
Immunogenic cell death (ICD) is the starting point of antitumor immunity, which could be induced by various treatments. [6,7] Reactive oxygen species (ROS)-based therapies such as radiotherapy, sonodynamic therapy (SDT), photodynamic therapy (PDT) and chemodynamic therapy (CDT), are commonly used to induce ICD effect. [[8], [9], [10], [11]] CDT has been defined as an in situ therapeutic strategy that using Fenton/Fenton-like reaction to generate highly toxic hydroxyl radicals (OH) in tumor sites. Among various Fenton agents, Mn shows incomparable advantages. It could not only induce TAAs release, but also enhance antigens presentation, promote T cells activation and infiltration, as well as facilitate tumor cells destruction by cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthetase (cGAS)-stimulator of interferon genes (STING) pathway activation. [[12], [13], [14]].
Unfortunately, the killing efficiency of cytotoxic T lymphocytes (CTLs), that play a key role in antitumor immunity, on tumor cells is limited in immunosuppressive tumor microenvironment (TME). The main reason for this phenomenon is that low extracellular pH could continuously incite T cells into an anergic state. [15] Due to continuous production of acidic metabolites by tumor cells, acid neutralizer strategy may be insufficient to reverse the immunosuppressive TME. [[16], [17], [18]] In comparison, disruption of tumor acid metabolism would be a good choice to polarize the immunosuppressive TME for immunological enhancement. [[19], [20]] Carbonic anhydrase IX (CAIX) is often regarded as a comtributor to TME acidification by hydration of carbon dioxide into protons. And it has also been proposed to accelerate tumor growth and metastasis. [[21], [22]] More importantly, CAIX is over-expressed on tumor cells, yet it hardly expressed on normal cells, making it a promising therapeutic target. [23].
In recent years, the immune enhancement effects of ascorbic acid has attracted more and more attention. As a cofactor of Ten-Eleven Translocation (TET) enzymes, ascorbic acid causes genome-wide demethylation that induces inconsistent effect in tumor cells and immune cells. [24] On one hand, ascorbic acid could increase tumor antigenicity by promoting endogenous retroviral expression. On the other hand, ascorbic acid could enhance the function of CTLs and antigen presenting cells (APC) by increasing 5-hydroxymethylcytosine (5hmC) level. [25] Moreover, ascorbic acid exhibits more obvious immune enhancement effect in the presence of TAAs, further amplifying ICD induced immune response. [26]. However, the instability of ascorbic acid have always limited its utilization. PA, one of ascorbic acid derivatives, has all the physiological activities of ascorbic acid and it could be converted into l-ascorbic acid in vivo. And the higher stability of PA makes it a potential candidate for enhanced immune response. Moreover, some reports have also indicated that PA at a much lower dose (20 mg/kg) was more effective than free ascorbic acid (intraperitoneal injection in high-dose 1 g/kg) for tumor treatment. [27,28].
Based on these observations, a core-shell nanoplatform for boosting all-immunity-cycle was constructed. Breifly, Mn-doped CaCO3 nanoparticles (Mn/CaCO3 NPs) and CAIX inhibitor SLC-0111 (SLC) were encapsulated into palmitoyl ascorbate (PA)-liposome (PL) to obtain Mn/CaCO3@PL/SLC. (Scheme 1). In tumor site, the pH-sensitive nanoplatform was decomposed in acidic compartments Then, released Mn, Ca, SLC-0111 and PA simultaneously executed different steps of the immunotherapy including initiation of cancer-immunity cycle via Mn and Ca triggered lipid peroxidation, remodeling of immunosuppresive TME and enhancement of effector T cells. In vitro and in vivo experiments verified that Mn/CaCO3@PL/SLC achieved outstanding synergistic immunotherapeutic effects in melanoma tumor models. It was worth emphasizing that Mn augmented the all-immunity-cycle by promoting cGAS-STING pathway activation. As revealed in this research, the all-immunity-phase-boosted strategy could certainly bring out an enhanced immunotherapy efficiency for tumor regression and metastasis prevention.
Section snippets
Materials
CaCl2·2H2O and NH4HCO3 were obtained from Sinopharm Chemical Reagent Co., Ltd., China. Dopamine and manganese chloride (MnCl2) were obtained from Sigma-Aldrich (St. Louis, MO, USA). 1,2-dioleoyl-sn-glycero-3-phosphate (sodium salt; DOPA) and palmitoyl ascorbate (PA) were obtained from Aladdin Chemistry Co., Ltd. 1-α-Phosphatidylcholine (PC) was purchased from CordenPharma (Plankstadt, Germany). Polyethylene glycol-conjugated 1,2-distearoyl-sn-glycero-3-phosphoetha-nolamine (DSPE-PEG2K) was
Mn/CaCO3@PL/SLC synthesis and characterization
To prepare Mn/CaCO3@PL/SLC nanoplatform, porous CaCO3 NPs were first synthetized by adopting one-pot gas diffusion process according to a reported method. [30] In this process, dopamine was firstly oxidized to form polydopamine (PDA) which could coordinate with Ca2+ to form Ca-PDA nanocomplexes. Menawhile, NH4HCO3 underwent decomposition to generate carbon dioxide (CO2). After dissolved into above solution, CO2 could interact with Ca2+ in form of carbonate ions, resulting in the deposition of
Conclusion
In this research, we constructed an all-immunity-phase-strengthened nanoplatform Mn/CaCO3@PL/SLC to simultaneously orchestrate host immune system and modulate immunesuppressive TME for tumor elimination. The immune enhancement process was dominated by Mn/CaCO3 and reinforced by SLC-0111 and PA in different ways. Mn/CaCO3 destroyed most tumor cells and triggered the release of TAAs for DCs maturation and T cells activation. SLC-0111 and PA synergistically facilitated T cells infiltration and
Credit author statement
The project was conceptually designed by Cuixia Zheng and Lei Wang.
The majority of the experiments were conducted by Cuixia Zheng, Qingling Song and Hongjuan Zhao, assisted by Yueyue Kong, Lingling Sun and Xinxin Liu.
Data analysis and interpretation were done by Cuixia Zheng, Qingling Song and Qianhua Feng.
The paper was prepared by Cuixia Zheng and Lei Wang.
All authors discussed the results and implications, and commented on the paper.
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 81673021, U1804183, 81573364, 81901878), Key Scientific Research Project (Education Department of Henan Province. 20HASTIT049), China Postdoctoral Science Fundation (2019M662553).
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