Data from Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination Article Swipe

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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 ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/1078-0432.c.6523436

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.

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CD8 Immunology Immunotherapy Antigen Microglia Cancer research Cytotoxic T cell Medicine Immune system Melanoma Biology Inflammation In vitro Biochemistry

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/1078-0432.c.6523436
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Title: Data from Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination

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Language: en

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Publication year: 2023

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Publication date: 2023-03-31

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Authors: 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

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Landing page: https://doi.org/10.1158/1078-0432.c.6523436

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Concepts: CD8, Immunology, Immunotherapy, Antigen, Microglia, Cancer research, Cytotoxic T cell, Medicine, Immune system, Melanoma, Biology, Inflammation, In vitro, Biochemistry

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abstract_inverted_index.analysis	59
abstract_inverted_index.antibody	153
abstract_inverted_index.antigens	4
abstract_inverted_index.blockade	79
abstract_inverted_index.blocking	143
abstract_inverted_index.detected	66
abstract_inverted_index.effector	187
abstract_inverted_index.efficacy	29, 107
abstract_inverted_index.elevated	67, 137, 185
abstract_inverted_index.findings	235
abstract_inverted_index.however,	142
abstract_inverted_index.immunity	209, 224
abstract_inverted_index.impaired	132
abstract_inverted_index.improved	171
abstract_inverted_index.melanoma	40, 244
abstract_inverted_index.restored	227
abstract_inverted_index.reversed	80, 168
abstract_inverted_index.systemic	207
abstract_inverted_index.therapy.	233
abstract_inverted_index.addition,	89
abstract_inverted_index.antitumor	208, 223
abstract_inverted_index.combining	229
abstract_inverted_index.cytotoxic	46
abstract_inverted_index.decreased	194
abstract_inverted_index.evaluated	102
abstract_inverted_index.exhibited	131
abstract_inverted_index.generally	13
abstract_inverted_index.increased	179
abstract_inverted_index.inhibitor	149
abstract_inverted_index.melanomas	112
abstract_inverted_index.microglia	71
abstract_inverted_index.radiation	95, 166, 232
abstract_inverted_index.responses	2, 47
abstract_inverted_index.secretion	69, 196
abstract_inverted_index.signaling	78, 145
abstract_inverted_index.survival.	157, 172
abstract_inverted_index.tolerance	81, 169
abstract_inverted_index.treatment	91, 174
abstract_inverted_index.1161–72.	255
abstract_inverted_index.accelerate	212
abstract_inverted_index.associated	177
abstract_inverted_index.collateral	16
abstract_inverted_index.monoclonal	152
abstract_inverted_index.periphery.	57
abstract_inverted_index.progressed	118
abstract_inverted_index.regulatory	190
abstract_inverted_index.Conversely,	158
abstract_inverted_index.attenuated,	14
abstract_inverted_index.combination	163
abstract_inverted_index.devastating	20
abstract_inverted_index.established	49
abstract_inverted_index.immunologic	104
abstract_inverted_index.originating	5
abstract_inverted_index.progression	214
abstract_inverted_index.recombinant	98
abstract_inverted_index.tolerogenic	115
abstract_inverted_index.vaccination	161, 230
abstract_inverted_index.consequently	211
abstract_inverted_index.contemporary	243
abstract_inverted_index.equivalently	117
abstract_inverted_index.significance	23
abstract_inverted_index.<i>Clin	251
abstract_inverted_index.Tumor-bearing	134
abstract_inverted_index.consequences.	21
abstract_inverted_index.cytotoxicity.	133
abstract_inverted_index.small-molecule	148
abstract_inverted_index.tumor-targeted	31
abstract_inverted_index.immunotherapies	32
abstract_inverted_index.tumor–bearing	64
abstract_inverted_index.antigen-directed	84
abstract_inverted_index.antigen-specific	124
abstract_inverted_index.<i>Listeria	99
abstract_inverted_index.Design:</b>	36
abstract_inverted_index.polyfunctionality	180
abstract_inverted_index.antigen–specific	160
abstract_inverted_index.hypothesis-generating	237
abstract_inverted_index.monocytogenes</i>	100
abstract_inverted_index.AACR</i>.</p></div>	257
abstract_inverted_index.unknown.</p><p><b>Experimental	35
abstract_inverted_index.model.</p><p><b>Results:</b>	110
abstract_inverted_index.<div>Abstract<p><b>Purpose:</b>	0
abstract_inverted_index.microglia.</p><p><b>Conclusions:</b>	198
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	20
sustainable_development_goals[0].id	https://metadata.un.org/sdg/3
sustainable_development_goals[0].score	0.7599999904632568
sustainable_development_goals[0].display_name	Good health and well-being
citation_normalized_percentile.value	0.17125563
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False