TNIK Inhibition Has Dual Synergistic Effects on Tumor and Associated Immune Cells

• Published in: Advanced biology 2022-08, Vol.6 (8), p.e2200030-n/a
• Main Authors: Kim, Jaehee, Oh, Juhyun, Peterson, Hannah M., Carlson, Jonathan C.T., Pittet, Mikael J., Weissleder, Ralph
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - metabolism; colorectal cancer; Colorectal Neoplasms - drug therapy; Disease Models, Animal; immunogenic cell death; Immunotherapy; kinase inhibitors; Mice; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors - pharmacology; TNIK
• ISSN: 2701-0198; 2701-0198
• DOI: 10.1002/adbi.202200030

Treatment with checkpoint inhibitors can be extraordinarily effective in a fraction of patients, particularly those whose tumors are pre‐infiltrated by T cells. In others, efficacy is considerably lower, which has led to interest in developing strategies for sensitization to immunotherapy. Using various colorectal cancer mouse models, it is shown that the use of Traf2 and Nck‐interacting protein kinase inhibitors (TNIKi) unexpectedly increases tumor infiltration by PD‐1+ CD8+ T cells, thus contributing to tumor control. This appears to happen by two independent mechanisms, by inducing immunogenic cell death and separately by directly activating CD8. The use of TNIKi achieves complete tumor control in 50% of mice when combined with checkpoint inhibitor targeting PD‐1. These findings reveal immunogenic properties of TNIKi and indicate that the proportion of colorectal cancers responding to checkpoint therapy can be increased by combining it with immunogenic kinase inhibitors. Dual synergistic effects of TNIK inhibition on tumor and associated immune cells are reported. TNIK inhibition increases tumor infiltration of PD‐1+ CD8+ T‐cells, thus contributing to tumor control. The use of TNIK inhibitors achieves complete tumor control in 50% of mice when combined with immune checkpoint inhibitor targeting PD‐1.