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.
Highlights
Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma
Whereas anti-tumor necrosis factor α (TNF) antibodies are used to cure immune-related adverse events (irAEs) associated with immunotherapies[24], whether TNF blockade affects the antimelanoma immune response triggered by immunotherapies remains to be determined
We investigated the impact of TNF deficiency on the therapeutic effect of anti-PD-1 on melanoma development
Summary
Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. Patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies. TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF has been shown to enhance the expression of programmed cell death ligand 1 (PD-L1) in cancer cells[17], including melanoma[15], triggering immunosuppression. Anti-PD-1 treatment is associated with increased TNF gene expression in melanoma samples from metastatic melanoma patients[23]. In this context, the contribution of TNF to the anti-melanoma immune response is unknown. TNF blockade/deficiency prevents PD-L1 and TIM-3 expression as well as AICD in CD8+ TILs, overcoming the resistance to anti-PD-1 in experimental melanoma
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