Blood-based Genomic and Cellular Determinants of Response to Neoadjuvant PD-1 Blockade in Patients with Non-Small-Cell Lung Cancer

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Background Despite the improved survival observed in PD-1/PD-L1 blockade therapy, there still is a lack of response to the anti-PD1 therapy for a large proportion of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC) Methods Transcriptomic profiling was performed on 57 whole blood samples from 31 NSCLC patients and 5 healthy donors, including both responders and non-responders received anti-PD-1 Tislelizumab plus chemotherapy, to characterize differentially expressed genes (DEGs), signature pathways, and immune cell subsets regulated during treatment. Mutations of oncogenic drivers were identified and associated with therapeutic outcomes in a validation cohort with 1661 cancer patients. These multi-level biomarkers were validated and compared across different methods, external datasets and multiple computational tools. Results NSCLC patients examined and achieved pathological complete response (pCR) were considered as responders or non-responders otherwise. Expression of hundreds DEGs (FDR p<0.05, fold change<-2 or >2) was changed in blood during neoadjuvant anti-PD-1 treatment, as well as in lung cancer tissue as compared to normal samples. Enriched PD-1-mediated pathways and elevated cell abundances of CD8 T cells and regulatory T cells were exclusively observed in responder blood samples. In an independent validation cohort of 1661 pan-cancer patients, a panel of 4 top ranked genetic alterations (PTCH1, DNMT3A, PTPRS, JAK2) identified from responders in discovery cohort were found positively associated with the overall survival (p<0.05). Conclusion These findings suggest peripheral blood-based biomarkers and cell subsets could be utilized to define the response to neoadjuvant PD-1 blockade in NSCLC patients and a set of novel gene mutations is strongly associated with the therapeutic outcome of cancer immunotherapy.