A Redox‐Responsive Nanovaccine Combined with A2A Receptor Antagonist for Cancer Immunotherapy

Abstract

In situ vaccination can trigger an antitumor immune response. However, the therapeutic effect is still limited since the high expression of adenosine binding to G protein‐coupled receptor A2AR induces an immunosuppressive effect. In this work, a new formulation is presented with the combination of a nanovaccine based on redox‐responsive polymer micelles and A2AR antagonist SCH58261. The micelles simultaneously encapsulate immunogenic cell death (ICD) inducer doxorubicin (DOX) and adjuvant toll‐like receptor 7 and 8 (TLR7/8) agonist R848, acting as the potent in situ vaccines. A high concentration of glutathione in tumor cells leads to the disintegration of these micelles, releasing DOX and R848 to mediate ICD, inducing the activation of dendritic cells and initiating an immune response. Meanwhile, A2AR antagonist SCH58261, a generation immune checkpoint blocker, inhibits the immunosuppressive adenosinergic pathway in the tumor microenvironment, activating natural killer (NK) cells and CD8+ T cells, and inhibiting the proliferation of regulatory T cells. Therefore, this formulation can trigger a robust systemic antitumor immune response.

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency

“…Other adjuvants, such as resiquimod (R848), a TLR7/8 agonist, can synergize with DOX to form the in situ vaccination, resulting in sixfolds of CD8 + T cells in the tumor microenvironment and a regression rate of 40% against 4T1 tumors. [117] ICD induced by chemotherapeutic agents in combination with ICIs, cytokines and immunoadjuvants has been demonstrated with a remarkable antitumor efficacy. Furthermore, chemotherapeutic agents combined with IDO inhibitors to modulate the tumor microenvironment, such as indoximod, [118] NLG919, [119] 1-methyl-tryptophan, [120] and small interfering RNAs [121] have also been demonstrated to inhibit tumor growth and prevent the metastasis.…”

“…Other adjuvants, such as resiquimod (R848), a TLR7/8 agonist, can synergize with DOX to form the in situ vaccination, resulting in sixfolds of CD8 + T cells in the tumor microenvironment and a regression rate of 40% against 4T1 tumors. [ 117 ]…”

Immunotherapy: Reshape the Tumor Immune Microenvironment

“…In addition to the combination of A2AR inhibitor and anti-PD-1/PD-L1, A2AR inhibitor was also combined with nanovaccine to activate CD8 T and NK cells and inhibit the proliferation of regulatory T cells. Thus, this strategy could trigger a robust systemic antitumor immune response ( 173 , 226 ). Furthermore, deletion of A2AR enhances the efficacy of CAR T cells ( 226 , 227 ).…”

“…Thus, this strategy could trigger a robust systemic antitumor immune response ( 173 , 226 ). Furthermore, deletion of A2AR enhances the efficacy of CAR T cells ( 226 , 227 ). Another way to implement this strategy is hyperoxygenation to improve cancer immunotherapies ( 69 , 224 ).…”

Immunosuppressive adenosine-targeted biomaterials for emerging cancer immunotherapy

“…Central to this therapeutic strategy is the synergistic amplification of immunomodulatory effects of adenosine inhibitors with therapies that induce ICD. Either the biomaterial carries chemotherapeutic agents capable of inducing ICD, such as doxorubicin (DOX), oxaliplatin (OXA), and paclitaxel (PTX), or the biomaterial is linked to light-induced reactivity that triggers ICD ( 7 , 34 – 36 , 41 ) ( Table 1 ). These treatments will directly kill tumor cells and induce the release of pro-inflammatory ATP and tumor antigens from tumor cells, subsequently initiating a specific antitumor immune response.…”