Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Autor: S. Brunelle, Mélanie Bentobji, Alessandro Moretta, Samuel Granjeaud, Gwenaelle Gravis, Flora Poizat, N. Salem, Palma Rocchi, Daniel Olive, Mathilde Guerin, Jeanne Thomassin-Piana, Francine Azario-Cheillan, Jochen Walz, Christine Pasero, Maria Paciencia-Gros
Přispěvatelé: Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Genova [Genova, Italy], Rocchi, Palma, Università degli studi di Genova = University of Genoa (UniGe)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cytotoxicity
Immunologic
Male
MESH: Killer Cells
Natural
Cancer Research
MESH: Cell Line
Tumor
MESH: Immune Tolerance
Oncology
medicine.medical_treatment
[SDV]Life Sciences [q-bio]
Biology
Immune tolerance
Natural killer cell
03 medical and health sciences
Interleukin 21
Prostate cancer
0302 clinical medicine
Cell Line
Tumor
MESH: Tumor Microenvironment
medicine
Immune Tolerance
Tumor Microenvironment
Humans
Prospective Studies
MESH: Cytotoxicity
Immunologic
Neoplasm Metastasis
Tumor microenvironment
MESH: Cytokines
Lymphokine-activated killer cell
MESH: Humans
Prostatic Neoplasms
Immunotherapy
medicine.disease
NKG2D
MESH: Neoplasm Metastasis
MESH: Male
MESH: Prospective Studies
[SDV] Life Sciences [q-bio]
Killer Cells
Natural
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
MESH: Prostatic Neoplasms
Immunology
Cytokines
Zdroj: Cancer Research
Cancer Research, American Association for Cancer Research, 2016, 76 (8), pp.2153-2165. ⟨10.1158/0008-5472.CAN-15-1965⟩
Cancer Research, 2016, 76 (8), pp.2153-2165. ⟨10.1158/0008-5472.CAN-15-1965⟩
ISSN: 0008-5472
1538-7445
Popis: The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFβ1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell–mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153–65. ©2016 AACR.
Databáze: OpenAIRE
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