224P - Lung cancer scRNA-seq analyses reveal potential mechanisms causing different efficacy of target therapy and immunotherapy between EGFR 19del and L858R lung adenocarcinoma

Background

Extensive clinical studies have demonstrated that patients having 19del mutation obtained a higher response rate and longer progression free survival (PFS) in the treatment of gefitinib or erlotinib than those with L858R mutation. Moreover, regarding immune checkpoint blockade (ICB), clinical evidence suggests that patients with the L858R mutation may get more benefit from ICB than 19del patients. These reports indicate that EGFR mutation subtypes can influence the response of patients to target therapy and immunotherapy. However, possible underlying mechanisms haven't been elucidated yet.

Methods

We applied single cell RNA sequencing (scRNA-seq) on 40 samples from EGFR L858R, 19del and wild-type patients to shed light on how distinct cellular status and signatures may influence the different clinical treatment responses for TKI and ICB among the EGFR mutation subtypes in LUAD.

Results

A group of cancer associated fibroblasts (CAFs) highly expressing HGF and FGF7 enriches in L858R patients (72.7% vs 35.7%, P < 0.001). These CAFs could dampen the efficacy of TKIs by secreting HGF and FGF7 to provide bypass survival signals for tumor cells under TKI pressure. Meanwhile, these CAFs also have strong communication with a group of tumor cell through TGF-β signaling pathway, which in turn enhances the secretion of HGF and FGF7 of CAF. Higher infiltration with the CAFs caused a shorter PFS in TKI treatment (P = 0.034). On the contrary, it was an immune favorable subgroup that facilitates T cell recruitment and activation. Consistently, CD8+T cells were closer to progenitor exhausted status in L858R patients while closer to terminally exhausted status in 19del patients. And higher infiltration with these CAFs prolonged the PFS of ICB treatment (P = 0.001). Also, 19del and L858R tumors exhibit varying degrees of dependence on EGFR signaling. GNAS expression was higher in L858R samples which could provide an alternative survival signal when EGFR signaling was inhibited.

Conclusions

Both CAF and tumor intrinsic differences caused different efficacy of TKI and ICB in 19del and L858R tumors. Targeting the factors might improve treatment efficacy in patients with specific EGFR genotypes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Key Research and Development Program of China (2022YFF0705300), National Natural Science Foundation of China (52272281, 32200535, 82172882, and 12090052), Clinical Research Project of Shanghai Pulmonary Hospital (FKLY20010), Young Talents in Shanghai (2019 QNBJ), Shanghai Shuguang Scholar, Supported by the Shanghai Municipal Science and Technology Major Project (2021SHZDZX0100) and the Fundamental Research Funds for the Central Universities, 2021 Science and Technology Think Tank Youth Talent Plan of China Association for Science and Technology, ‘Dream Tutor’ Outstanding Young Talents Program (fkyq1901), National Key Research and Development Program of China (2021YFF1201200 and 2021YFF1200900), Ministry of Science and Technology of the People’s Republic of China (STI2030 Major Projects 2021ZD0201900).

Disclosure

All authors have declared no conflicts of interest.