Adaptive resistance to anti-PD1 therapy by tim-3 upregulation is mediated by the PI3k-akt pathway in head and neck cancer

Gulidanna Shayan, Raghvendra Srivastava, Jing Li, Nicole Schmitt, Lawrence P. Kane, Robert L. Ferris

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL. We observed that PD-1+ and Tim-3+ coexpression was associated with a more exhausted phenotype, with the highest PD-1 levels on TIL coexpressing Tim-3. Dampened Akt/S6 phosphorylation in these PD-1CTim-3C TIL, when the PD-1 pathway was ligated, suggested that signaling cross-talk could lead to escape through Tim-3 expression. Indeed, PD-1 blockade of human HNSCC TIL led to further Tim-3 upregulation, supporting a circuit of compensatory signaling and potentially permitting escape from anti-PD-1 blockade in the tumor microenvironment. Also, in a murine HNC tumor model that is partially responsive to anti-PD-1 therapy, Tim-3 was upregulated in TIL from persistently growing tumors. Significant antitumor activity was observed after sequential addition of anti-Tim-3 mAb to overcome adaptive resistance to anti-PD-1 mAb. This increased Tim-3-mediated escape of exhausted TIL from PD-1 inhibition that was mediated by phospho-inositol-3 kinase (PI3K)/Akt complex downstream of TCR signaling but not cytokine-mediated pathways. Taken together, we conclude that during PD-1 blockade, TIL upregulate Tim-3 in a PI3K/Aktdependent manner, providing further support for dual targeting of these molecules for more effective cancer immunotherapy.

Original languageEnglish (US)
Article numbere1261779
Issue number1
StatePublished - Jan 9 2017


  • Head and neck cancer
  • Immunotherapy
  • Monoclonal antibody
  • PD-1
  • Tim-3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology


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