Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy.
J Clin Invest
; 128(11): 5137-5149, 2018 11 01.
Article
em En
| MEDLINE
| ID: mdl-30188869
ABSTRACT
Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mostardas de Fosforamida
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Neoplasias da Próstata
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Linfócitos T
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Adenocarcinoma
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Imunoterapia
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Neoplasias Experimentais
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Nitroimidazóis
Limite:
Animals
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos