PURPOSE: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of @entity5 -targeted immunotherapies is largely unknown. EXPERIMENTAL DESIGN: The B16 @entity19 @entity320 model was used to compare cytotoxic responses against established @entity5 in the CNS and in the periphery. Cytokine analysis of tissues from @entity1313 -bearing @entity19 detected elevated @entity641 secretion from microglia and in the serum and @entity641 signaling blockade reversed tolerance of @entity5 antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant @entity5125 was evaluated for immunologic activity and efficacy in this model. RESULTS: CNS @entity320 were more tolerogenic than equivalently progressed @entity5 outside the CNS as antigen-specific CD8 T cells were deleted and exhibited @entity137 . Tumor-bearing @entity19 had elevated serum levels of @entity641 ; however, blocking @entity641 signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, @entity5 antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased @entity641 secretion from microglia. CONCLUSIONS: These data suggest that CNS @entity5 may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in @entity320 models as well as @entity1 trials. Clin Cancer Res; 22(5); 1161-72.   2015 AACR.

Systemic Tolerance Mediated by Melanoma XXXX Is Reversible by Radiotherapy and Vaccination.

@entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['impaired cytotoxicity'] @entity1313 :: ('MESH:D001932', 'Disease') :: ['brain tumor'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'tumors'] @entity641 :: ('21803(Tax:10090)', 'Gene') :: ['TGFb'] @entity19 :: ('10090', 'Species') :: ['mice', 'murine'] @entity5125 :: ('1639', 'Species') :: ['Listeria monocytogenes'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma', 'contemporary melanoma', 'melanomas']
@entity1313 :: (MESH:D001932,Disease) :: ['Brain Tumors']
