Biological advances have resulted in immunotherapeutic regimens that target co-inhibitory receptors such as PD-1 to reverse T-cell exhaustion and promote anti-tumor responses that eradicate human tumors. However, despite its success in many cancer types, a substantial number of patients do not respond to PD-1/PD-L1 blockade. This includes patients with the B-cell malignancy follicular lymphoma, suggesting that co-blockade of co-inhibitory receptors may be necessary to achieve optimal anti-tumor T-cell responses.
In a study recently published in Clinical Cancer Research (journal impact factor 9.6), the authors demonstrate the power of using high dimensional flow cytometry analysis of follicular lymphoma tumors to identify new targets for checkpoint blockade.
Characterization of co-inhibitory receptor expression patterns was combined with functional assessment of T-cell receptor-induced signaling responses. This approach successfully identified TIGIT as the main co-inhibitory receptor. Follicular lymphoma CD8 T cells had reduced production of IFN-γ as well as highly reduced T-cell receptor induced phosphorylation of MAPK ERK. Reduced T-cell function correlated with TIGIT expression and could be fully restored by in vitro culture in absence of TIGIT ligands. TIGIT-expressing CD8 T cells also commonly co-expressed PD-1. The results provide new insights into mechanisms that contribute to immune suppression, and suggest that TIGIT blockade, potentially in co-blockade with PD-1, may be a promising strategy for improved immunotherapy.
The study, published online in Clinical Cancer Research on December 7th, is a collaboration between OUS, UiO and several international partners, including Ronald Levy at Stanford University and Jonathan Irish at Vanderbilt University in the US.
T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling.
Josefsson SE, Huse K, Kolstad A, Beiske K, Pende D, Steen CB, Inderberg EM, Lingjærde OC, Østenstad B, Smeland EB, Levy R, Irish JM, Myklebust JH.
Clin Cancer Res. 2017 Dec 7. pii: clincanres.2337.2017. doi: 10.1158/1078-0432.CCR-17-2337.
Home page of the Lymphomas & Lymphocyte biology group, headed by Erlend B. Smeland
Previous news about June Myklebost:
Oslo University Hospital has awarded 6 excellent articles for the second half-year of 2016
Awarded for: first authorship on article in Blood (IF = 13.2)
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R (2016)
Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling
Blood, 129 (6), 759-770