Milk fat globule - epidermal growth factor - factor 8 protein (MFG-E8) is an important mediator of the tolerogenic functions of GM-CSF, and a dominant-negative RGE mutant augments the therapeutic potential of irradiated, GM-CSF-secreting tumor vaccines (GVAX) in the MFG-E8-negative B16 melanoma model. The frequent expression of MFG-E8 in various solid and hematological malignancies, however, prompted us to investigate the effect of the RGE mutant in a MFG-E8-positive transplantable breast tumor model. Here, we report that MFG-E8 blockade augmented anti-tumor humoral responses and modulated immune infiltrates at vaccination sites, which was associated with defective phagocytosis and clearance of apoptotic tumor cells. The RGE mutant enhanced the therapeutic potential of two irradiated, GM-CSF-secreting vaccines and improved protection correlated with augmented tumor-specific IgG1 and IgG2a antibody responses as well as increased ratios of T effectors to Tregs in TILs. These findings are consistent with the notion that MFG-E8 blockade potentiates anti-tumor responses through the preferential expansion of effector over regulatory T cells. Our data also validate the use of the RGE mutant to achieve therapeutically effective MFG-E8 blockade even in the context of tumors and vaccines that express high levels of endogenous MFG-E8.

CD73 est un ecto-enzyme qui a été associé à la suppression de l'immunité anti-tumorale. Ses valeurs pronostiques et thérapeutiques ont été mises de l'avant dans plusieurs types de cancer. La première hypothèse du projet est que l'expression de CD73 dans la tumeur prédit le pronostic des patients atteints du cancer de la prostate. L'expression de CD73 a été étudiée par immunofluorescence dans des échantillons de tumeur. Puis, des analyses univariées et multivariées ont été conduites pour déterminer si l'expression de CD73 permet de prédire la récidive biochimique des patients. Nous avons déterminé que CD73 prédit indépendamment le pronostic des patients atteints du cancer de la prostate. De plus, nous avons déterminé que son expression dans le tissu normal adjacent ou dans la tumeur prédit différemment la survenue de la récidive biochimique. La deuxième hypothèse est que l'inhibition de CD73 permet d'améliorer l'efficacité d'un vaccin thérapeutique contre le cancer de la prostate. L'effet d'un vaccin de type GVAX a été étudié dans des souris CD73KO ou en combinaison avec un anticorps ciblant CD73. Nous avons observé que l'efficacité du vaccin était augmentée dans les souris où CD73 était absent. Cependant, la combinaison avec l'anti-CD73 n'a pas permis d'améliorer l'efficacité. / The ectoenzyme CD73 has been associated with suppression of anti-tumor immunity. Its prognostic and therapeutic values have been highlighted in many types of cancer. The first hypothesis of this project is that tumor CD73 expression predicts the prognosis of prostate cancer patients. CD73 expression was determined by immunofluorescence in tumor tissues. Univariates and multivariates analysis were conducted to determine if CD73 expression could predict patients' biochemical recurrence. We determined that CD73 predicts independently the prognosis of prostate cancer patients. Moreover, we determined that CD73 expression in normal adjacent tissue or in the tumor predicts differently the occurrence of biochemical recurrence. The second hypothesis is that CD73 blockade enhances the efficacy of a therapeutic vaccine against prostate cancer. The GVAX-like vaccine was studied in CD73KO mice or in combination with an antibody against CD73. We observed that the vaccine was more efficient in mice where CD73 was absent. However, the combination with the anti-CD73 did not enhances the efficacy of the vaccine.