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Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

ABSTRACT: Chemotherapy turns tumor cells into "tumor vaccines" by immunogenic cell death (ICD). However, it remains a challenge to exploit chemotherapy-induced "tumor vaccines" for solid cancer immunotherapy due to the inefficient effector T cells activation and tumor microenvironment immunosuppression. Here, a matrix metalloprotease 2 responsive liposome (PEG-FA-Lip) composed of cleavable PEG chains covering the folate (FA)-modified liposome is developed to deliver ICD inducer doxorubicin. In breast cancer-bearing mice, PEG-FA-Lip targets both 4T1 breast cancer cells and M2-tumor associated macrophages (M2-TAMs) via FA-receptor mediated endocytosis, resulting in abundant "tumor vaccines" and efficient elimination of M2-TAMs. The combination of local cytosine-phosphate-guanine (CpG) therapy facilitates PEG-FA-Lip induced "tumor vaccines" to effectively arouse systematic effector T cells immune response through promoting dendritic cell maturation and immunostimulatory cytokines secretion. The simultaneous elimination of M2-TAMs ensures the activated effector T cells exert antitumor immunity within tumor via decreasing immunosuppressive cytokines secretion and tumor infiltration of Treg cells. After receiving the combined treatment, 30.1% of breast cancer-bearing mice (initial tumor volume > 100 mm3) achieves the goal of tumor eradication. Remarkably, this combination therapy greatly inhibits lung metastasis and controls the growth of already metastasized breast cancers (initial tumor volume > 100 mm3).

SUBMITTER: Deng C

PROVIDER: S-EPMC6425447 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

Deng Caifeng C Zhang Quan Q Jia Mengdi M Zhao Jin J Sun Xun X Gong Tao T Zhang Zhirong Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190130 6

Chemotherapy turns tumor cells into "tumor vaccines" by immunogenic cell death (ICD). However, it remains a challenge to exploit chemotherapy-induced "tumor vaccines" for solid cancer immunotherapy due to the inefficient effector T cells activation and tumor microenvironment immunosuppression. Here, a matrix metalloprotease 2 responsive liposome (PEG-FA-Lip) composed of cleavable PEG chains covering the folate (FA)-modified liposome is developed to deliver ICD inducer doxorubicin. In breast canc ...[more]

PMID: 30937266

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Project description:BackgroundAlthough immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.MethodsWe designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.ResultsIM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development.ConclusionsBy simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.

Dataset Information

Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

Publications

Tumors and Their Microenvironment Dual-Targeting Chemotherapy with Local Immune Adjuvant Therapy for Effective Antitumor Immunity against Breast Cancer.

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