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

F Bertrand, A Montfort, E Marcheteau, C Imbert… - Nature …, 2017 - nature.com
F Bertrand, A Montfort, E Marcheteau, C Imbert, J Gilhodes, T Filleron, P Rochaix…
Nature communications, 2017nature.com
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 α (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 …
Abstract
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 α (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+ tumor-infiltrating 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.
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