American Association for Cancer Research
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Supplemental Figure 2 from Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination

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posted on 2023-03-31, 18:23 authored by Christopher M. Jackson, Christina M. Kochel, Christopher J. Nirschl, Nicholas M. Durham, Jacob Ruzevick, Angela Alme, Brian J. Francica, Jimmy Elias, Andrew Daniels, Thomas W. Dubensky, Peter Lauer, Dirk G. Brockstedt, Emily G. Baxi, Peter A. Calabresi, Janis M. Taube, Carlos A. Pardo, Henry Brem, Drew M. Pardoll, Michael Lim, Charles G. Drake

Brain tumors are more tolerogenic than flank or lung tumors. (A) Representative FACS plots from tumor draining lymph nodes of mice with B16-OVA brain, flank, or lung tumors. (B) Summary graphs of the percentage of daughter cells producing IFN-γ recovered from the tumor draining lymph nodes of mice with B16-OVA brain, flank, or lung tumors (5 mice/group).

Funding

NIH

the Patrick C. Walsh Fund, the OneInSix Foundation, the Prostate Cancer Foundation, and the Melanoma Research Association

Howard Hughes Medical Fellows Research Program

The Bart McLean Fund for Neuroimmunology Research-Project Restore

WW Smith Foundation

History

ARTICLE ABSTRACT

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 tumor-targeted immunotherapies is largely unknown.Experimental Design: 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. Clin Cancer Res; 22(5); 1161–72. ©2015 AACR.