Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination

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 Grace Baxi, Peter Calabresi, Janis M Taube, Carlos A Pardo-Villamizar, Henry Brem, Andrew Mark Pardoll, Michael Lim, Charles G. Drake

Research output: Contribution to journalArticle

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 TGFb secretion from microglia and in the serum and TGFb 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.

Original languageEnglish (US)
Pages (from-to)1161-1172
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2016

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Central Nervous System Neoplasms
Brain Neoplasms
Melanoma
Vaccination
Radiotherapy
Central Nervous System
Microglia
Neoplasm Antigens
T-Lymphocytes
Immunity
CD8 Antigens
Neoplasms
Experimental Melanomas
Survival
Histocompatibility Antigens Class II
Listeria monocytogenes
Regulatory T-Lymphocytes
Serum
Immunotherapy
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Jackson, C. M., Kochel, C. M., Nirschl, C. J., Durham, N. M., Ruzevick, J., Alme, A., ... Drake, C. G. (2016). Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clinical Cancer Research, 22(5), 1161-1172. https://doi.org/10.1158/1078-0432.CCR-15-1516

Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. / Jackson, Christopher M.; Kochel, Christina M.; Nirschl, Christopher J.; Durham, Nicholas M.; Ruzevick, Jacob; Alme, Angela; Francica, Brian J.; Elias, Jimmy; Daniels, Andrew; Dubensky, Thomas W.; Lauer, Peter; Brockstedt, Dirk G.; Baxi, Emily Grace; Calabresi, Peter; Taube, Janis M; Pardo-Villamizar, Carlos A; Brem, Henry; Pardoll, Andrew Mark; Lim, Michael; Drake, Charles G.

In: Clinical Cancer Research, Vol. 22, No. 5, 01.03.2016, p. 1161-1172.

Research output: Contribution to journalArticle

Jackson, CM, Kochel, CM, Nirschl, CJ, Durham, NM, Ruzevick, J, Alme, A, Francica, BJ, Elias, J, Daniels, A, Dubensky, TW, Lauer, P, Brockstedt, DG, Baxi, EG, Calabresi, P, Taube, JM, Pardo-Villamizar, CA, Brem, H, Pardoll, AM, Lim, M & Drake, CG 2016, 'Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination', Clinical Cancer Research, vol. 22, no. 5, pp. 1161-1172. https://doi.org/10.1158/1078-0432.CCR-15-1516
Jackson, Christopher M. ; Kochel, Christina M. ; Nirschl, Christopher J. ; Durham, Nicholas M. ; Ruzevick, Jacob ; Alme, Angela ; Francica, Brian J. ; Elias, Jimmy ; Daniels, Andrew ; Dubensky, Thomas W. ; Lauer, Peter ; Brockstedt, Dirk G. ; Baxi, Emily Grace ; Calabresi, Peter ; Taube, Janis M ; Pardo-Villamizar, Carlos A ; Brem, Henry ; Pardoll, Andrew Mark ; Lim, Michael ; Drake, Charles G. / Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 5. pp. 1161-1172.
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T1 - Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination

AU - Jackson, Christopher M.

AU - Kochel, Christina M.

AU - Nirschl, Christopher J.

AU - Durham, Nicholas M.

AU - Ruzevick, Jacob

AU - Alme, Angela

AU - Francica, Brian J.

AU - Elias, Jimmy

AU - Daniels, Andrew

AU - Dubensky, Thomas W.

AU - Lauer, Peter

AU - Brockstedt, Dirk G.

AU - Baxi, Emily Grace

AU - Calabresi, Peter

AU - Taube, Janis M

AU - Pardo-Villamizar, Carlos A

AU - Brem, Henry

AU - Pardoll, Andrew Mark

AU - Lim, Michael

AU - Drake, Charles G.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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 TGFb secretion from microglia and in the serum and TGFb 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.

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