Tumor-Targeted Gene Silencing IDO Synergizes PTT-Induced Apoptosis and Enhances Anti-tumor Immunity

Abstract

Background: Photothermal therapy (PTT) has been demonstrated to be a promising cancer treatment approach because it can be modulated to induce apoptosis instead of necrosis via adjusting irradiation conditions. Recently, an abscopal anti-tumor immunity has been highlighted, in which PTT on the primary tumor also induced repression of distant tumors. In PTT cancer treatments, the mechanism and the role of immune checkpoints to enhance anti-tumor immunity needs to be investigated. Methods: We prepared a multi-functional gold nanorod reagent, GMPF-siIDO, that is composed of gold nanorods (GNRs) that act as the nano-platform and photothermal sensitizer; folic acid (FA) as the tumor-targeting moiety; and IDO-specific RNA (siIDO) as an immune-stimulator functionality for inducing anti-tumor immunity. For this study, we adjusted the irradiation condition of PTT to induce apoptosis and to silence the immune checkpoint indoleamine 2,3 dioxygeonase (IDO), simultaneously. Results: Our studies provide evidence that photothermal effects kill tumor cells mainly via inducing apoptosis, which can significantly improve antitumor immunity when IDO was down-regulated in TME through significant increases of localized CD8 + and CD4 + lymphocytes in tumor tissue, the downregulation of CD8 + and CD4 + lymphocyte apoptosis, and the upregulation of antitumor cytokines, TNF-α and IFN-γ. Conclusion: In this study, we, for the first time, validated the role of IDO as a negative regulator for both PTT-induced tumor cell apoptosis and anti-tumor immunity; IDO is a critical immune checkpoint that impedes PTT while combination of gene knockdown of IDO in TME enhances anti-tumor efficacy of PTT.

D-MT Prompts the Anti-Tumor Effect of Oxaliplatin by Inhibiting IDO Expression in A Mouse Model of Colon Cancer

“…IDO has been proven to catalyze the oxidative catabolism of Trp to Kyn, and regulate immune responses by impairing the survival and activity of T cells 44,45 . IDO has therefore become a therapeutic target for cancer that could either be used alone or in combination with other treatments for tumors 46,47 . However, our results showed that oxaliplatin could inhibit tumor growth and increase the apoptosis of tumor cells, but could also increase the expression of IDO, which might interfere with the therapeutic effect of oxaliplatin.…”

Improvement of Gold Nanorods in Photothermal Therapy: Recent Progress and Perspective

“…GNRs nanoplatforms functionalized with antibodies (Chu et al, 2017), peptides (Singh et al, 2016), proteoglycan, vitamins (Papaioannou et al, 2018;Zhang et al, 2020), and aptamers realize selective targeting via binding to the specific receptors of tumor cells or the TME. To overcome the disadvantages of natural antibodies, such as poor stability, comparably complicated preparation process, and low affinity toward nonimmunogenic targets (Ye and Mosbach 2008), molecular imprinting technology was exploited to construct sialic acid (SA)-imprinted GNRs, which exhibited high affinity to cancer cells overexpressed SA (Yin et al, 2017).…”

“…IDO is an immunosuppressive factor that can weaken the body's antitumor immunity. This system uses siIDO to silence gene expression to achieve the effect of immunotherapy (Zhang et al, 2020). Although the specificity of PTT is greatly improved, damage to surrounding tissues can be inevitable and trigger certain inflammatory reactions.…”

Modulating expression of inhibitory and stimulatory immune ‘checkpoints’ using nanoparticulate-assisted nucleic acid delivery

“…To develop an siIDO platform for in vivo testing Zhang et al developed a folate targeted, gold nanorod based system, for combined siRNA delivery and photothermal therapy [70]. As photothermal therapy elevates the level of IDO, it was speculated that the combination with IDO silencing would result in synergistic effects.…”