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Application of Bionanomaterials in Tumor Immune Microenvironment Therapy.

ABSTRACT: Targeted therapy for the cancer immune system has become a clinical reality with remarkable success. Immune checkpoint blockade therapy and chimeric antigen receptor T-cell (CAR-T) immunotherapy are clinically effective in a variety of cancers. However, the clinical utility of immunotherapy in cancer is limited by severe off-target toxicity, long processing time, limited efficacy, and extremely high cost. Bionanomaterials combined with these therapies address these issues by enhancing immune regulation, integrating the synergistic effects of different molecules, and, most importantly, targeting and manipulating immune cells within the tumor. In this review, we will summarize the most current researches on bionanomaterials for targeted regulation of tumor-associated macrophages, myeloid-derived suppressor cells, dendritic cells, T lymphocyte cells, and cancer-associated fibroblasts and summarize the prospects and challenges of cell-targeted therapy and clinical translational potential in a tumor immune microenvironment in cancer treatment.

SUBMITTER: Wang J

PROVIDER: S-EPMC7892227 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Application of Bionanomaterials in Tumor Immune Microenvironment Therapy.

Wang Jiawei J Bao Yan Y Yao Yandan Y Yao Yandan Y

Journal of immunology research 20210210

Targeted therapy for the cancer immune system has become a clinical reality with remarkable success. Immune checkpoint blockade therapy and chimeric antigen receptor T-cell (CAR-T) immunotherapy are clinically effective in a variety of cancers. However, the clinical utility of immunotherapy in cancer is limited by severe off-target toxicity, long processing time, limited efficacy, and extremely high cost. Bionanomaterials combined with these therapies address these issues by enhancing immune reg ...[more]

PMID: 33628850

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Project description:Tumor cell senescence is a common outcome of anticancer therapy. Here we investigated how therapy-induced senescence (TIS) affects tumor-infiltrating leukocytes (TILs) and the efficacy of immunotherapy in melanoma.Tumor senescence was induced by AURKA or CDK4/6 inhibitors (AURKAi, CDK4/6i). Transcriptomes of six mouse tumors with differential response to AURKAi were analyzed by RNA sequencing, and TILs were characterized by flow cytometry. Chemokine RNA and protein expression were determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Therapeutic response was queried in immunodeficient mice, in mice with CCL5-deficient tumors, and in mice cotreated with CD137 agonist to activate TILs. CCL5 expression in reference to TIS and markers of TILs was studied in human melanoma tumors using patient-derived xenografts (n = 3 patients, n = 3 mice each), in AURKAi clinical trial samples (n = 3 patients, before/after therapy), and in The Cancer Genome Atlas (n = 278). All statistical tests were two-sided.AURKAi response was associated with induction of the immune transcriptome (P = 3.5 x 10-29) while resistance inversely correlated with TIL numbers (Spearman r = -0.87, P < .001). AURKAi and CDK4/6i promoted the recruitment of TILs by inducing CCL5 secretion in melanoma cells (P ? .005) in an NF-?B-dependent manner. Therapeutic response to AURKAi was impaired in immunodeficient compared with immunocompetent mice (0% vs 67% tumors regressed, P = .01) and in mice bearing CCL5-deficient vs control tumors (P = .61 vs P = .02); however, AURKAi response was greatly enhanced in mice also receiving T-cell-activating immunotherapy (P < .001). In human tumors, CCL5 expression was also induced by AURKAi (P ? .02) and CDK4/6i (P = .01) and was associated with increased immune marker expression (P = 1.40 x 10-93).Senescent melanoma cells secret CCL5, which promotes recruitment of TILs. Combining TIS with immunotherapy that enhances tumor cell killing by TILs is a promising novel approach to improve melanoma outcomes.

Project description:BackgroundNeoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC.MethodsClinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided.ResultsTwo hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival.ConclusionsNeoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients' antitumor immune response.

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Application of Bionanomaterials in Tumor Immune Microenvironment Therapy.

Publications

Application of Bionanomaterials in Tumor Immune Microenvironment Therapy.

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