TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma

被引：313

作者：

Bertrand, Florie ^{[1
,2
]}

Montfort, Anne ^{[1
,2
]}

Marcheteau, Elie ^{[1
,2
,3
,4
]}

Imbert, Caroline ^{[1
,2
,3
,4
]}

Gilhodes, Julia ^{[5
]}

Filleron, Thomas ^{[5
]}

Rochaix, Philippe ^{[5
]}

Andrieu-Abadie, Nathalie ^{[1
,2
]}

Levade, Thierry ^{[1
,2
,3
,4
,6
]}

Meyer, Nicolas ^{[1
,3
,4
,5
,7
,8
]}

Colacios, Celine ^{[1
,2
,3
,4
]}

Segui, Bruno ^{[1
,2
,3
,4
]}

机构：

[1] INSERM, UMR 1037, CRCT, F-31037 Toulouse, France

[2] Equipe Labellisee Ligue Canc, F-31037 Toulouse, France

[3] Univ Toulouse III Paul Sabatier, F-31062 Toulouse, France

[4] Univ Fed Toulouse Midi Pyrenees, 41 Allee Jules Guesde, F-31000 Toulouse, France

[5] Inst Univ Canc, F-31059 Toulouse, France

[6] CHU Purpan, Inst Federatif Biol, Lab Biochim, F-31059 Toulouse, France

[7] Hop Larrey, F-31059 Toulouse, France

[8] Oncopole, F-31059 Toulouse, France

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

TUMOR-NECROSIS-FACTOR; T-CELL DYSFUNCTION; ADAPTIVE RESISTANCE; UNTREATED MELANOMA; ANTITUMOR IMMUNITY; REGULATORY-CELLS; PD-1; BLOCKADE; UP-REGULATION; LUNG-CANCER; TIM-3;

D O I：

10.1038/s41467-017-02358-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor alpha (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumorinfiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.

引用

页数：13

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