Generation and characterization of an anti-PD1-resistant lune cancer line (TUM2P.1040)

Immunotherapies targeting PD1/PDL1 have shown unprecedented rates of durable clinical responses in patients with melanoma and lung cancer. However, there is a substantial portion of patients who do not respond to these therapies. The goal of this study is to generate an anti-PD1-resistant tumor line and identify mechanisms of resistance, which should provide novel insights to extend the benefit of immunotherapies. A preclinical lung cancer model was generated by inoculation of a murine lung cancer cell line 344SQ (containing p53 and kras mutations) into syngeneic 129SV/ev mice. Anti-mouse PD1 antibodies were administrated at day 4 post tumor inoculation for a total of 5 doses. The anti-PD1 resistant line was successfully generated after sequential in vivo passaging of a nonresponsive tumor followed by anti-PD1 treatment. Upon the anti-PD1 treatment, the parental line showed 70% tumor reduction, whereas the resistant line showed only 12% tumor reduction. PDL1 expression did not alter in the resistant line. Instead, anti-PD1 treatment remarkably increased MHC I expression in the parental line, whereas the resistant line showed significantly lower MHC I and II expression and failed to upregulate MHC I upon anti-PD1 treatment. The parental and resistant lines showed distinct profiles of tumor-infiltrating immune cells and costimulatory molecule expression in vivo . Next we will study if inducing MHC expression through radiation or HDAC inhibitors will overcome anti-PD1 resistance.