AUTHOR=Dutta Nikita , Rohlin Anna , Eklund Ella A. , Magnusson Maria K. , Nilsson Frida , Akyürek Levent M. , Torstensson Per , Sayin Volkan I. , Lundgren Anna , Hallqvist Andreas , Raghavan Sukanya TITLE=Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer JOURNAL=Frontiers in Oncology VOLUME=Volume 12 - 2022 YEAR=2023 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1073457 DOI=10.3389/fonc.2022.1073457 ISSN=2234-943X ABSTRACT=Abstract Objectives: Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This pilot study aimed to investigate the value of combining immune and genetic variables analyzed within 3–4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response. Materials and Methodology: Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months’ assessment after the start of therapy. Results: We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood of responders. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders. Conclusion: Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.