Abstract 356P
Background
Immune checkpoint inhibitors have shown significant therapeutic responses against lung cancer. However, reinvigoration of antitumor immunity remains a big challenge.
Methods
We use flow cytometry to test the capacity of 640 tyrosine kinase inhibitors (TKIs) to increase the expression of CD69 and ICOS in CD8+T cells. In vitro and in vivo studies were further used to validate the T cell activation effect of screened TKIs. Crispr-cas9 knockout was used to identify the potential targets of screened TKIs.
Results
The screening of 640 tyrosine kinase inhibitors yielded two major hits, merestinib and WRG-28. Merestinib and WRG-28 caused a dose-dependent increase in the expression of CD69, ICOS, and the production of interferon-γ (IFN-γ) in mouse primary CD8+T cells. Merestinib and WRG-28 also decreased the expression of PD-1 and TIGIT (T cell immunoglobulin and ITIM domain) in activated mouse primary CD8+T cells. Mechanistically, merestinib and WRG-28 share the same target, DDR2 (discoidin domain receptor tyrosine kinase 2), knockout of DDR2 phenocopied these effects. Furthermore, merestinib and WRG-28 caused the rapid (10 min) activation of the T-cell receptorproximal signaling kinases, as detectable by immunoblot detection of activating phosphorylations affecting LAT (on tyrosine residue 220) and LCK (on tyrosine 394). Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the merestinib or WRG-28 treatment suppressed the tumor growth of TC-1 lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo.
Conclusions
In conclusion, merestinib and WRG-28 restrain lung cancer immunosurveillance. DDR2 is a potential novel T-cell immune checkpoint.
Legal entity responsible for the study
Huazhong Univercity of Science and Technology, Wuhan, China.
Funding
National Natural Science Foundation of China (no. 82070099, no. 82330003 and no.82300124).
Disclosure
All authors have declared no conflicts of interest.