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Updated: Feb 16, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma
Florie Bertrand1,2, Anne Montfort1,2, Elie Marcheteau1,2,3,4
1INSERM UMR 1037, CRCT, 31037, Toulouse, France.
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.
Insights
Blocking tumor necrosis factor (TNF) enhances anti-PD-1 cancer therapy by improving CD8+ T cell response and reducing immune suppression. This combination strategy shows promise for solid tumors.
Area of Science:
- Immunology
- Oncology
- Cancer immunotherapy
Background:
- Anti-programmed cell death-1 (PD-1) antibodies revolutionized melanoma treatment but face challenges with response rates and relapse.
- Immune-related adverse events associated with anti-PD-1 therapy can be managed with anti-tumor necrosis factor α (TNF) antibodies.
- The impact of anti-TNF antibodies on anti-cancer immunity is not fully understood.
Purpose of the Study:
- To investigate the synergistic effects of TNF or TNFR1 blockade with anti-PD-1 therapy on anti-cancer immune responses.
- To elucidate the mechanisms by which TNF signaling influences the efficacy of anti-PD-1 immunotherapy.
- To explore the potential of combining anti-PD-1 and anti-TNF therapies for solid cancers.
Main Methods:
- Utilized mouse melanoma models to study the effects of TNF/TNFR1 blockade on CD8+ tumor-infiltrating lymphocytes (TILs).
- Assessed the impact of TNF blockade on anti-PD-1-induced TIL cell death, PD-L1, and TIM-3 expression.
- Correlated TNF expression with PD-L1 and TIM-3 expression in human melanoma specimens.
Main Results:
- TNF or TNFR1 blockade synergizes with anti-PD-1 to enhance anti-cancer immune responses in solid tumors.
- TNF blockade prevents anti-PD-1-induced T cell death and reduces the expression of PD-L1 and TIM-3.
- TNF expression positively correlates with PD-L1 and TIM-3 expression in human melanoma.
Conclusions:
- Combined blockade of TNF and PD-1 enhances anti-cancer immunity by preserving CD8+ TILs and modulating immune checkpoint molecules.
- This study provides a strong mechanistic rationale for developing combination therapies using anti-PD-1 and anti-TNF agents in cancer patients.
- Targeting TNF signaling represents a promising strategy to overcome resistance and improve outcomes in anti-PD-1 immunotherapy.
