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Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

ABSTRACT: Lack of tumor-infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid-derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for "immune-cold" tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor-targeting and light-responsive-penetrable nanoplatform (Apt/PDGs_^s@pMOF) is developed to elicit intratumoral infiltration of cytotoxic T cells (CTLs) and reeducate immunosuppressive microenvironment simultaneously. In particular, porphyrinic metal-organic framework (pMOF)-based photodynamic therapy (PDT) induces tumor immunogenic cell death (ICD) to promote CTLs intratumoral infiltration and hot "immune-cold" tumor. Upon being triggered by PDT, the nearly 10 nm adsorbed drug-loaded dendrimer de-shields from the nanoplatform and spreads into the deeper tumor, eliminating MDSCs and reversing immunosuppression, eventually reinforcing immune response. Meanwhile, the designed nanoplatform also has a systemic MDSC inhibition effect and moderate improvement of overall antitumor immune responses, resulting in effective suppression of distal tumors within less significant immune-related adverse effects (irAEs) induced.

SUBMITTER: Chen Q

PROVIDER: S-EPMC7503208 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

Chen Qinjun Q He Yongqing Y Wang Yu Y Li Chao C Zhang Yujie Y Guo Qin Q Zhang Yiwen Y Chu Yongchao Y Liu Peixin P Chen Hongyi H Zhou Zheng Z Zhou Wenxi W Zhao Zhenhao Z Li Xiaomin X Sun Tao T Jiang Chen C

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200729 17

Lack of tumor-infiltration lymphocytes (TILs) and resistances by overexpressed immunosuppressive cells (principally, myeloid-derived suppressor cells (MDSCs)) in tumor milieu are two major challenges hindering the effectiveness of immunotherapy for "immune-cold" tumors. In addition, the natural physical barrier existing in solid cancer also limits deeper delivery of drugs. Here, a tumor-targeting and light-responsive-penetrable nanoplatform (Apt/PDGs<sub>^</sub>s@pMOF) is developed to elicit int ...[more]

PMID: 32995118

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Project description:Background and aimsImmunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood.MethodsData for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry.ResultsWe were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors.ConclusionIn this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.

Dataset Information

Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

Publications

Penetrable Nanoplatform for "Cold" Tumor Immune Microenvironment Reeducation.

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