High baseline PD-1+ CD8 T Cells and TIGIT+ CD8 T Cells in circulation associated with response to PD-1 blockade in patients with non-small cell lung cancer
Nikita Dutta, Johanna Svensson, George Abi Saad, Marielle Mello, Ella Ä. Eklund, Ilayda Altinönder, Per Torstensson, Volkan I. Sayin, Anna Rohlin, Hervé Luche, Andreas Hallqvist, Sukanya Raghavan
Abstract
Abstract Blockade of PD-1 or its ligand PD-L1 with antibodies revolutionized treatment for stage III and IV non-small cell lung cancer (NSCLC) since FDA approval in 2015. However, resistance to PD-1/PD-L1 blockade remains a challenge, highlighting the need for biomarkers. This study analyzed 36 stage III and IV NSCLC patients, classified as responders or non-responders by iRECIST criteria. Peripheral blood mononuclear cells collected at baseline and post-treatment were examined for surface and intracellular markers via flow cytometry. CITE sequencing of CD8 T cells from three patients and plasma ctDNA analysis from 13 patients was performed using an ultrasensitive barcoding and next-generation sequencing method. Phenotypic analysis of CD8 T cells revealed higher TIGIT and PD-1 expression at baseline in responders compared to non-responders. Long-term responders (> 21 months) exhibited increased TCF-1 + PD-1 + CD8 T cell frequencies relative to shorter-term responders (> 15 months) and non-responders. CITE sequencing revealed intrinsic differences in immune regulation pathways between responders and non-responders. Finally, non-responders showed elevated and increasing ctDNA levels post-treatment, correlating with declining TCF-1 + PD-1 + CD8 T cells. Our data suggests combining CD8 T cell analysis with ctDNA dynamics could identify promising biomarkers for monitoring clinical response and treatment efficacy to PD-1/PD-L1 blockade in NSCLC.