Boost Infiltration and Activity of T Cells via Inhibiting Ecto-5'-nucleotidase (CD73) Immune Checkpoint to Enhance Glioblastoma Immunotherapy.

in ACS nano by Hao Zhang, Li Yang, Mengxiao Han, Yaobao Han, Zhilin Jiang, Qing Zheng, Jun Dong, Tingting Wang, Zhen Li

TLDR

  • The study found that a protein called ecto-5-nucleotidase (CD73) in glioblastoma multiforme (GBM) helps the tumor to hide from the immune system. The study used special particles called Au@CuSe nanoparticles (ACS NPs) to reduce the amount of CD73 in the tumor. This allowed the immune system to better attack the tumor and reduce its size. The study also found that combining CD73 inhibition with chemoradiotherapy (a treatment that uses radiation and chemicals to kill cancer cells) further improved the effectiveness of the treatment.

Abstract

The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@CuSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(,-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8T and CD4T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.

Overview

  • The study aims to investigate the role of ecto-5-nucleotidase (CD73) in glioblastoma multiforme (GBM) and develop a novel strategy to enhance GBM immunotherapy. The study uses versatile Au@CuSe nanoparticles (ACS NPs) to inhibit CD73 expression and reduce the production of adenosine (ADO) in GBM. The study demonstrates that the inhibition of CD73 enhances antitumor T cell infiltration and activity, leading to a significant reduction in tumor size. The study's findings suggest that modulation of CD73-mediated tumor immunosuppression is an important strategy for improving the outcome of GBM immunotherapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions. The study found that the inhibition of CD73 using ACS NPs significantly increased the infiltration and activity of antitumor T cells, leading to a significant reduction in tumor size. The study also found that the combination of CD73 inhibition with chemoradiotherapy further enhanced the efficacy of GBM immunotherapy. The study's findings suggest that modulation of CD73-mediated tumor immunosuppression is an important strategy for improving the outcome of GBM immunotherapy.

Implications and Future Directions

  • The study's findings suggest that modulation of CD73-mediated tumor immunosuppression is an important strategy for improving the outcome of GBM immunotherapy. The study's findings also suggest that the combination of CD73 inhibition with chemoradiotherapy further enhances the efficacy of GBM immunotherapy. The study's findings highlight the importance of developing novel strategies to enhance GBM immunotherapy. Future research directions could include the development of other CD73 inhibitors and the exploration of the combination of CD73 inhibition with other immunotherapies.
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