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

  • Nat Commun. 2017 Dec 22;8(1):2256. doi: 10.1038/s41467-017-02358-7.
Florie Bertrand  1  2 ,  Anne Montfort  1  2 ,  Elie Marcheteau  1  2  3  4 ,  Caroline Imbert  1  2  3  4 ,  Julia Gilhodes  5 ,  Thomas Filleron  5 ,  Philippe Rochaix  5 ,  Nathalie Andrieu-Abadie  1  2 ,  Thierry Levade  1  2  3  4  6 ,  Nicolas Meyer  1  3  4  7 ,  Céline Colacios  1  2  3  4 ,  Bruno Ségui  8  9  10  11
Affiliations
  • 1. INSERM UMR 1037, CRCT, 31037, Toulouse, France.
  • 2. Equipe Labellisée Ligue Contre Le Cancer, 31037, Toulouse, France.
  • 3. Université Toulouse III - Paul Sabatier, 31062, Toulouse, France.
  • 4. Université Fédérale de Toulouse Midi-Pyrénées, 41 Allée Jules Guesde, 31000, Toulouse, France.
  • 5. Institut Universitaire du Cancer, 31059, Toulouse, France.
  • 6. Laboratoire de Biochimie, Institut Fédératif de Biologie, CHU Purpan, 31059, Toulouse, France.
  • 7. Institut Universitaire du Cancer, Toulouse, Hôpital Larrey et Oncopôle, 31059, Toulouse, France.
  • 8. INSERM UMR 1037, CRCT, 31037, Toulouse, France. [email protected].
  • 9. Equipe Labellisée Ligue Contre Le Cancer, 31037, Toulouse, France. [email protected].
  • 10. Université Toulouse III - Paul Sabatier, 31062, Toulouse, France. [email protected].
  • 11. Université Fédérale de Toulouse Midi-Pyrénées, 41 Allée Jules Guesde, 31000, Toulouse, France. [email protected].
PMID: 29273790 DOI: 10.1038/s41467-017-02358-7
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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