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Multifunctional Nanoregulator Reshapes Immune Microenvironment and Enhances Immune Memory for Tumor Immunotherapy.

ABSTRACT: Hypoxia leads to up-regulation of PD-L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO2 particles and small molecular IPI549 is developed, which can reshape the tumor immune microenvironment (TIME) to unleash the immune system. The intravenously administered nanoregulator effectively accumulates in tumor sites to alleviate hypoxia via oxygen-generating reduction of MnO2 and to inhibit PI3K? on MDSCs via IPI549 release in the tumor microenvironment (TME), which results in concurrent downregulation of PD-L1 expression, polarization of tumor associated macrophages (TAMs) toward pro-inflammatory M1-like phenotype (tumor-suppressive), enhanced infiltration of CD4+ helper T lymphocytes (Th cells), and cytotoxic CD8+ T lymphocytes (Tc cells), and suppressed infiltration of regulatory T lymphocytes (Treg cells) for effective tumor immunotherapy. Furthermore, the local generation of Mn2+ in TME allows tumor-specific magnetic resonance imaging (MRI). More excitingly, the nanoregulator-reshaped TIME is effectively reserved due to the synergistic effect of hypoxia alleviation and MDSC PI3K? inhibition, leading to remarkable post-medication inhibition of tumor re-growth and metastasis in an animal study.

SUBMITTER: Yu M

PROVIDER: S-EPMC6702652 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Multifunctional Nanoregulator Reshapes Immune Microenvironment and Enhances Immune Memory for Tumor Immunotherapy.

Yu Meng M Duan Xiaohui X Cai Yujun Y Zhang Fang F Jiang Shuqi S Han Shisong S Shen Jun J Shuai Xintao X

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190617 16

Hypoxia leads to up-regulation of PD-L1 and decreases T lymphocyte infiltration, thus boosting immunotherapeutic resistance of tumors. Moreover, tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) correlate with potent immune suppressive activity and resistance to the immune checkpoint blocking (ICB) in tumor sites. Here, a multifunctional nanoregulator incorporating MnO<sub>2</sub> particles and small molecular IPI549 is developed, which can reshape the tumor immun ...[more]

PMID: 31453054

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death with a median survival time of 6-12 months. Most patients present with disseminated disease and the majority are offered palliative chemotherapy. With no approved treatment modalities for patients who progress on chemotherapy, we explored the effects of long-term gemcitabine administration on the tumor microenvironment to identify potential therapeutic options for chemorefractory PDAC. Using a combination of mouse models, primary cell line-derived xenografts, and established tumor cell lines, we first evaluated chemotherapy-induced alterations in the tumor secretome and immune surface proteins by high throughput proteomic arrays. In addition to enhancing antigen presentation and immune checkpoint expression, gemcitabine consistently increased the synthesis of CCL/CXCL chemokines and TGF?-associated signals. These secreted factors altered the composition of the tumor stroma, conferring gemcitabine resistance to cancer-associated fibroblasts in vitro and further enhancing TGF?1 biosynthesis. Combined gemcitabine and anti-PD-1 treatment in transgenic models of murine PDAC failed to alter disease course unless mice also underwent genetic or pharmacologic ablation of TGF? signaling. In the setting of TGF? signaling deficiency, gemcitabine and anti-PD-1 led to a robust CD8+ T-cell response and decrease in tumor burden, markedly enhancing overall survival. These results suggest that gemcitabine successfully primes PDAC tumors for immune checkpoint inhibition by enhancing antigen presentation only following disruption of the immunosuppressive cytokine barrier. Given the current lack of third-line treatment options, this approach warrants consideration in the clinical management of gemcitabine-refractory PDAC. SIGNIFICANCE: These data suggest that long-term treatment with gemcitabine leads to extensive reprogramming of the pancreatic tumor microenvironment and that patients who progress on gemcitabine-based regimens may benefit from multidrug immunotherapy.See related commentary by Carpenter et al., p. 3070 GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/15/3101/F1.large.jpg.

Dataset Information

Multifunctional Nanoregulator Reshapes Immune Microenvironment and Enhances Immune Memory for Tumor Immunotherapy.

Publications

Multifunctional Nanoregulator Reshapes Immune Microenvironment and Enhances Immune Memory for Tumor Immunotherapy.

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