Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination.
OBJECTIVE
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 tumor-targeted immunotherapies is largely unknown.


METHODS
The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.


RESULTS
CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor 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 TGFβ secretion from microglia.


CONCLUSIONS
These data suggest that CNS tumors 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 contemporary melanoma models as well as human trials.
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
Christopher M
CM
Jackson
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Christina M
CM
Kochel
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Christopher J
CJ
Nirschl
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Nicholas M
NM
Durham
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
Jacob
J
Ruzevick
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Angela
A
Alme
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Brian J
BJ
Francica
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Jimmy
J
Elias
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Andrew
A
Daniels
Aduro Biotech, Berkeley, California.
Thomas W
TW
Dubensky
Aduro Biotech, Berkeley, California.
Peter
P
Lauer
Aduro Biotech, Berkeley, California.
Dirk G
DG
Brockstedt
Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
Emily G
EG
Baxi
Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
Peter A
PA
Calabresi
Department of Dermatology, Johns Hopkins University, Baltimore, Maryland. Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
Janis M
JM
Taube
Department of Neurology, Johns Hopkins University, Baltimore, Maryland. Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
Carlos A
CA
Pardo
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland. Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
Henry
H
Brem
Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
Drew M
DM
Pardoll
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland. cdrake@jhmi.edu mlim3@jhmi.edu.
Michael
M
Lim
Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland. cdrake@jhmi.edu mlim3@jhmi.edu.
Charles G
CG
Drake
D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology; D001932:Brain Neoplasms / Q000097:blood / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D016543:Central Nervous System Neoplasms / Q000097:blood / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008546:Melanoma, Experimental / Q000097:blood / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D017628:Microglia / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000097:blood*; D014611:Vaccination
D000951:Antigens, Neoplasm; D016212:Transforming Growth Factor beta