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

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.

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

“…5 Finally, some preclinical data suggest that TNF blockade may potentiate an antitumor response in combination with PD-1 inhibition. 6 Consequently, the current data do not inform the extent of the risk, if any, of therapeutic TNF blockade to tumour control mediated by immune checkpoint inhibitor therapy.…”

“…There are some preclinical data to suggest that tumor necrosis factor (TNF) blockade does not have an adverse effect on tumor outcomes. Indeed, in one of these studies, a synergistic antitumor benefit is even postulated . To date, however, clinical data has been limited by the exclusion of patients requiring immunosuppression for concurrent autoimmune conditions or transplant management from most clinical trials.…”

Differential effects of corticosteroids and anti‐TNF on tumor‐specific immune responses: implications for the management of irAEs

“…Notably, TNF‐signaling has been shown to impair CD8 + T cell immune responses against melanoma by triggering TNF‐R1‐mediated cell death in activated CD8 + T cells . Moreover, the capacity of TNF to induce PD‐L1 and TIM‐3 expression on CD8 + TILs has been demonstrated in preclinical studies . Here we show that low to moderate doses of steroids had a negative impact on the activation and killing ability of TILs in vitro , however, high doses of steroids did not completely abrogate activation or killing ability of TILs.…”

“…Indeed, TNFα can act as a cytotoxic cytokine during CD8 + T cell‐mediated tumor‐killing and can enhance the activation, proliferation and cytokine secretion of CD8 + T cells . On the other hand, TNFα can act as an immunosuppressive cytokine acting on regulatory immune cell function . Notably, TNF‐signaling has been shown to impair CD8 + T cell immune responses against melanoma by triggering TNF‐R1‐mediated cell death in activated CD8 + T cells .…”

“…24 On the other hand, TNFα can act as an immunosuppressive cytokine acting on regulatory immune cell function. 24,25 Notably, TNFsignaling has been shown to impair CD8 + T cell immune responses against melanoma by triggering TNF-R1-mediated cell death in activated CD8 + T cells. 24 Moreover, the capacity of TNF to induce PD-L1 and TIM-3 expression on CD8 + TILs has been demonstrated in preclinical studies.…”