title: Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer.
abstract: 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 co-expression was associated with a more exhausted phenotype, with the highest PD-1 levels on TIL co-expressing Tim-3. Dampened Akt/S6 phosphorylation in these PD-1+Tim-3+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/Akt-dependent manner, providing further support for dual targeting of these molecules for more effective cancer immunotherapy.
authors.affiliation: School of Medicine, Tsinghua University , Beijing, China.
authors.forename: Gulidanna
authors.initials: G
authors.lastname: Shayan
authors.affiliation: Department of Otolaryngology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Raghvendra
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: School of Medicine, Tsinghua University , Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Department of Immunology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kane
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
keywords: Head and neck cancer; PD-1; Tim-3; immunotherapy; monoclonal antibody