Defining non-small cell lung cancer tumor microenvironment changes at primary and acquired immune checkpoint inhibitor resistance using clinical and real-world data.

Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy in non-small cell lung cancer (NSCLC) and extensive research has been conducted to explore biomarkers predictive of ICI response. However, the impact of ICI on the tumor and tumor microenvironment (TME) at primary and acquired resistance states is understudied due to the difficulty of collecting tissue biopsies at disease progression. In this study, we leveraged clinical and real-world data to study ICI resistance. Data used in this work consist of treatment outcome information and tissue RNA-Seq data from advanced-stage NSCLC cohorts from three sources: Tempus RWE database (3 cohorts), one cohort from CANOPY-1 (NCT03631199), a phase 3 clinical trial in 1L NSCLC, and one cohort curated from the academic initiative Stand Up 2 Cancer (SU2C). Our results indicate higher interferon gamma (IFNγ) and T cell exhaustion in patients' tumors at acquired resistance and low levels of B cell and dendritic cells (DC) expression at primary resistance. The lower B cell and DC levels may be primarily driven by prior treatment with a platinum-based chemotherapy regimen. Baseline transcriptomics data additionally suggest that innate immune cells may play an anti-tumor role in PD-L1<1% patients, whereas IFNγ and T cell inflammation are more predictive of ICI treatment outcome in PD-L1<1% patients. Conclusions: Our study suggests a clear divergence of the TME in patients with primary vs. acquired resistance, and a potential role of myeloid cells in the PD-L1 negative population. These findings shed light on potential next-generation therapies to overcome ICI resistance.