Cytokine secretion associated with the clearance of apoptotic bodies in renal cell carcinoma patients.
The factors determining the outcome of immunotherapy in metastatic renal cell carcinoma (RCC) patients remain elusive. Macrophages from normal donors that phagocytose apoptotic cells secrete the immunosuppressive cytokine IL-10 in vitro. Conversely, IL-10 genetic deletion enhances the immunogenicity of apoptotic tumor cells in vivo. Elevated pre-treatment levels of IL-10 are associated with an unfavorable outcome of RCC. We examined whether the ability to release IL-10 by macrophages from RCC patients that phagocytosed apoptotic cells correlated with the outcome of immunotherapy. To this aim, we derived macrophages from 30 patients with metastatic RCC and from 21 healthy subjects (11 sex- and age-matched healthy controls and 10 younger donors). Patients either had a clinical response after immunotherapy, with a median survival after treatment of more than 18 months (n = 16), or were beginning immunotherapy after diagnosis of metastatic disease (n = 14). Macrophages from responding patients challenged with apoptotic cells released significantly less IL-10 than controls (p = 0.0075) and recently diagnosed patients (p = 0.0198), as ascertained by a 2-sided Student's t-test. This was not because macrophages from responding patients lost the ability to secrete IL-10, because antibody opsonization of apoptotic cells rescued IL-10 secretion. In contrast, macrophages from all groups of donors released similar amounts of TNF-alpha. The failure in IL-10 secretion by engulfing macrophages of responding subjects may exalt the immunogenicity of dying tumor cells, contributing to the success of immunotherapy.
Laboratory of Tumor Immunology and Cancer Immunotherapy and Gene Therapy Program, H. San Raffaele Scientific Institute, Milan, Italy.
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Bondanza
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Rovere
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Borri
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Caremoli
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Guidetti
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Citterio
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Consogno
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Zimmermann
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Rugarli
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Manfredi
D000328:Adult; D000367:Age Factors; D000368:Aged; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016753:Interleukin-10 / Q000096:biosynthesis; D019169:Jurkat Cells; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010587:Phagocytosis; D016896:Treatment Outcome
D016207:Cytokines; D016753:Interleukin-10