Progress and Prospects of Regulatory Functions Mediated by Nitric Oxide on Immunity and Immunotherapy

Hu, Qian; Shi, Jingyu; Jiao, Zaibin; Wang, Yi; Guo, Yuanyuan; Zhang, Zhiping

doi:10.1002/adtp.202100032

Cited by 11 publications

(9 citation statements)

References 253 publications

(243 reference statements)

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“…Clearly, the concentration of .NO, the stability, the triggering signals for its synthesis, the cells involved and its source, its intracellular and extracellular effects, etc., play major roles on the outcome manifested by the various T cell subsets. Several reports in the literature have discussed the roles of iNOS and .NO in T cell differentiation in the thymus and the periphery, its role in the regulation of CD4 and CD8 T cells, Th1, Th2, and Th17 and immunity to infections, cancer and autoimmune diseases [5,[121][122][123][124].…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Regulation of T Cells in Cancer by Nitric Oxide

Navasardyan

Bonavida

2021

Cells

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The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

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Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Regulation of T Cells in Cancer by Nitric Oxide

Navasardyan

Bonavida

2021

Cells

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“…These results showed the considerable potential of BMS-SNAP-MOF for NO therapy of cancer. [56] Small 2022, 18, 2107732…”

Section: In Vitro Gsh-responsive No Release and Cytotoxicitymentioning

confidence: 99%

GSH‐Responsive Metal–Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy

Xiao

et al. 2022

Small

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renal cell carcinoma (RCC), [2] and nonsmall cell lung carcinoma (NSCLC). [3] Through active or passive means, tumor immunotherapy induces the body to produce a tumor-specific immune response which suppresses the tumor progression and prevents the tumor recurrence or metastasis. [4][5][6] Strategies reported for tumor immunotherapy so far mainly involved immune checkpoint blockade (ICB), [7] adoptive cell transfer therapy (ACT), [8] tumor-specific vaccines, [9] and application of small molecular immunemodulating drugs. [10] However, most immunotherapy methods often encounter the great challenge of not being effective enough for many tumors of which a large amount do not respond in the clinic, [11,12] requiring advanced tumor immunotherapy methods to be developed.Among various tumor immunotherapy strategies, inhibition of the indoleamine-2,3-dioxygenase (IDO) is drawing great attention at present because of its critical role in mediating tumor immune evasion, and some inspiring studies were reported. [13][14][15] Admittedly, IDO catalyzes the degradation of amino acid l-tryptophan (Trp) into the metabolite l-kynurenine (Kyn), which suppresses cytotoxic T lymphocytes (CTL) and activates regulatory T (Treg) cells. [16,17] The strong immunomodulatory functions of IDO can be attributed Immunotherapy brings great benefits for tumor therapy in clinical treatments but encounters the severe challenge of low response rate mainly because of the immunosuppressive tumor microenvironment. Multifunctional nanoplatforms integrating effective drug delivery and medical imaging offer tremendous potential for cancer treatment, which may play a critical role in combinational immunotherapy to overcome the immunosuppressive microenvironment for efficient tumor therapy. Here, a nanodrug (BMS-SNAP-MOF) is prepared using glutathione (GSH)-sensitive metal-organic framework (MOF) to encapsulate an immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) inhibitor BMS-986205, and the nitric oxide (NO) donor s-nitrosothiol groups. The high T1 relaxivity allows magnetic resonance imaging to monitor nanodrug distribution in vivo. After the nanodrug accumulation in tumor tissue via the EPR effect and subsequent internalization into tumor cells, the enriched GSH therein triggers cascade reactions with MOF, which disassembles the nanodrug to rapidly release the IDO-inhibitory BMS-986205 and produces abundant NO. Consequently, the IDO inhibitor and NO synergistically modulate the immunosuppressive tumor microenvironment with increase CD8 + T cells and reduce Treg cells to result in highly effective immunotherapy.In an animal study, treatment using this theranostic nanodrug achieves obvious regressions of both primary and distant 4T1 tumors, highlighting its application potential in advanced tumor immunotherapy.

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“…Nitric oxide (NO), as a short-lived physiological and pathological messenger, has been reported to regulate vasodilation, cell proliferation, migration and death, and the reversion of drug resistance. − Of late, it has been reported that plasma-generated reactive nitrogen species such as NO radical induced ICD in melanoma and pancreatic tumors. , Additionally, NO has also been reported to inhibit immune escape via various mechanisms such as interfering with PD-L1 activation, downregulating HIF-1α, or relieving hypoxia. − Hence, it is speculated that NO serves as an all-in-one immunomodulatory agent that can induce ICD and simultaneously dampen the ITME of tumors for self-amplifying immune therapy independent of other immunomodulatory strategies. However, the inherent instability and short lifespan of NO dramatically limited its applications. − To this end, many efforts have been devoted to developing NO delivery carriers, but these have many issues such as low NO storage, premature NO release, or insufficient NO leakage. − It is still a big challenge to construct a robust nanosystem that possesses abundant NO storage and precisely unleashes NO on demand.…”

Section: Introductionmentioning

confidence: 99%

Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy

Huang

Zhong

et al. 2022

ACS Appl. Mater. Interfaces

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The lack of tumor immunogenicity coupled with the presence of tumor immunosuppression severely hinders antitumor immunity, especially in the treatment of "immune cold" tumors. Here, we have developed a drug-free and NIR-enabled nitric oxide (NO)-releasing nanogasholder (NO PS @BP) composed of an outer cloak of nitrate-containing polymeric NO donor and an inner core of black phosphorus (BP) as the energy converter to spatiotemporally regulate NO-mediated tumor microenvironment remodeling and achieve multimodal therapy. Following NIR-irradiation, BPinduced photothermia and its intrinsic reducing property accelerate NO release from the outer cloak, by which the instantaneous NO burst concomitant with mild photothermia, on the one hand, induces immunogenic cell death (ICD), thereby provoking antitumor responses such as the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs); on the other hand, it reverses tumor immunosuppression via Treg inhibition, M2 macrophage restraint, and PD-L1 downregulation, further strengthening antitumor immunity. Therefore, this drug-free NO PS @BP by means of multimodal therapy (NO gas therapy, immune therapy, photothermal therapy) realizes extremely significant curative effects against primary and distant tumors and even metastasis in B16F10 tumor models, providing a new modality to conquer immune cold tumors by NO-potentiated ICD and immunosuppression reversal.

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Progress and Prospects of Regulatory Functions Mediated by Nitric Oxide on Immunity and Immunotherapy

Cited by 11 publications

References 253 publications

Regulation of T Cells in Cancer by Nitric Oxide

Regulation of T Cells in Cancer by Nitric Oxide

GSH‐Responsive Metal–Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy

Black Phosphorus-Synergic Nitric Oxide Nanogasholder Spatiotemporally Regulates Tumor Microenvironments for Self-Amplifying Immunotherapy

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