Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy

Autor: Chen Chen, Rui Ju, Juan Li, Jing Shi, Lei Guo, Qingzhu Wang, Caiying Ye, Dechang Zhang
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
Apoptosis
CD8-Positive T-Lymphocytes
Lymphocyte Activation
Mice
0302 clinical medicine
IDO1
Cancer immunotherapy
PD-1
Tumor Cells
Cultured
Tumor Microenvironment
Immunology and Allergy
Melanoma
Kynurenine
Mice
Inbred BALB C
biology
Chemistry
CAI
Tryptophan
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Drug Therapy
Combination
Immunotherapy
Antibody
Research Article
Immunology
Antineoplastic Agents
Mice
Transgenic
lcsh:RC254-282
03 medical and health sciences
Immune system
medicine
Animals
Humans
Indoleamine-Pyrrole 2
3
-Dioxygenase
Cell Proliferation
Pharmacology
Tumor microenvironment
AhR
T lymphocyte
Triazoles
Flavones
Mice
Inbred C57BL
IFN
030104 developmental biology
Receptors
Aryl Hydrocarbon
Cancer cell
Cancer research
biology.protein
CD8
Zdroj: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-14 (2019)
Journal for Immunotherapy of Cancer
ISSN: 2051-1426
DOI: 10.1186/s40425-019-0725-7
Popis: Background Cancer immunotherapy has generated significant excitement, mainly as a result of the development of immune checkpoint inhibitors. The blockade of PD-1 or its ligand with antibodies has resulted in impressive clinical efficacy. However, a subset of patients does not respond to biologic therapeutics, and another subset suffers from severe immune-related adverse events in certain cases. The modulation of the immune system with small molecules might yield surprising benefits. Methods CD8+ cells were obtained through a magnetic cell sorting system (MACS), and their capabilities for IFN-γ release and PD-1 expression were analyzed. The in vitro effects of drugs were studied in a coculture system of tumor cells and activated CD8+ cells. We further isolated the primary tumor cells in tumor-bearing mice treated with CAI, DMF, 1-MT or a combination (CAI and DMF/CAI and 1-MT) and analyzed the percentages of CD8+ T cells and PD-1+CD8+ T cells among TILs. The selective anti-tumor immune reactions of the two drug combinations were confirmed in a coculture system consisting of B16-OVA cells and OVA-specific CTLs derived from OT-1 transgenic mice. The anti-tumor effects of the single drugs or combined therapies were assessed according to their capability to slow tumor growth and extend the life span of tumor-bearing mice, and they were compared with the effects of PD-1 antibody. Results CAI increased IFN-γ release from activated T cells, which might strengthen the anti-proliferative and anti-metastatic effects on cancer cells. However, CAI also stimulated IDO1-Kyn metabolic circuitry in the tumor microenvironment and facilitated tumor cell immune evasion. Combining CAI with 1-MT or DMF disrupted PD-1 expression and promoted IFN-γ production in CD8+ T cells, and it also increased T lymphocyte infiltration in the tumor microenvironment, inhibited tumor growth and prolonged the life spans of tumor-bearing mice. Conclusion Inhibitors of the IDO1-Kyn-AhR pathway could abolish the negative effects of CAI on CD8+ T cells and result in complementary and beneficial anti-tumor immune effects. The combination of CAI with 1-MT or DMF greatly augmented the ability of CD8+ T cells to kill malignant cells and showed a strong anti-cancer capability that was superior to that of either of the single agents was is comparable with that of anti-PD-1 antibody. The combinations of small molecules utilized in this study may serve as valuable new immunotherapy strategies for cancer treatment. Electronic supplementary material The online version of this article (10.1186/s40425-019-0725-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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