62P - Ecto-CRT induction of NKp46 surface expression increases osimertinib-resistant lung cancer’s sensitivity to NK cells

Background

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have dramatically changed lung cancer treatment modalities and improved EGFR-mutated non-small cell lung cancer (NSCLC) patients’ prognosis over the past two decades. Third-generation EGFR-TKI, Osimertinib, has resulted in impressive success both in the first-line treatment setting and as a salvage therapy in the presence of the T790M secondary mutation. However, most patients inevitably develop resistance, with therapeutic options limited to platinum-based chemotherapy. There is a need for new treatment strategies.

Methods

We evaluated the utility of NK92 and NK92 armed with CAR-EGFR against TKI-sensitive and TKI-resistant lung cancer cells.

Results

Osimertinib-resistant cells H1975OR are more sensitive to NK cell attack than TKI-sensitive H1975 cells. H1975OR cells express less EGFR than H1975 and have further reduced EGFR expression than H1975 cells after EGFR-CAR NK cell attacks, suggesting antigen loss. Additionally, EGFR-CAR NK cell treatment did not reduce the sensitivity of Osimertinib and irradiation efficacy on lung cancer cells. Investigation of the increased killing of Osimertinib-resistant H1975OR by NK cells revealed NK cell surface accumulation of NKp46, a crucial natural cytotoxicity receptor (NCRs), on NK92 and EGFR CAR-NK92 cells stimulated after contact with Osimertinib-resistant cells H1975OR but not TKI sensitive H1975 cells. Externalized calreticulin (Ecto-CRT), which translocates from the endoplasmic reticulum (ER) to the cell membrane during ER stress, is a recently discovered ligand for NKp46. Our results show Osimertinib-induced Ecto-CRT expression in lung adenocarcinoma cells and that Osimertinib-resistant lung cancer cells also express more Ecto-CRT than sensitive cells. Ecto-CRT expression is associated with the induction of NKp46 on NK cells, leading to enhanced killing of Osimertinib-resistant cells.

Conclusions

Osimertinib-resistant lung cancer cell expression of Ecto-CRT induces the accumulation of NKp46 on engaged NK cell surface, leading to the enhanced killing of Osimertinib-resistant lung cancer cells.

Legal entity responsible for the study

The authors.

Funding

Zhejiang Province Health Department 2024ky205.

Disclosure

All authors have declared no conflicts of interest.