Tracking Peripheral Memory T Cell Subsets in Advanced Non-Small Cell Lung Cancer Treated with Hypofractionated Radiotherapy and PD-1 Blockade in the ABSCOPAL-1 Clinical Trial

Abstract

Background: Hypofractionated radiotherapy (HFRT) or chemotherapy combined with programmed death-1 (PD-1) blockade has achieved good clinical control in advanced non-small cell lung cancer (NSCLC). However, the effects of the distinct cell-killing mechanisms induced by radiotherapy and chemotherapy on immune memory remain unclear. We compared T memory subset differentiation in responders and non-responders treated with HFRT combined with PD-1 blockade to those in responders treated with chemo-immunotherapy. Methods: Thirty-eight patients with advanced NSCLC were enrolled in the trial. The frequencies of naive (Tn; CD45RA+CCR7+ ), central memory (Tcm; CD45RA–CCR7+), effector memory (Tem; CD45RA–CCR7–), and effector memory RA (TemRA; CD45RA+ CCR7–) T cell subsets and PD-1 expression were analyzed in CD4+ and CD8+ T cells using flow cytometry on single-cell suspensions from peripheral blood samples. Subsets were compared between healthy control and untreated NSCLC groups; among partial response, stable disease, and progressive disease groups treated using HFRT+PD-1 blockade; and between those treated with chemo-immunotherapy pre- and post-treatment. The correlations of memory T cell subsets and PD-1 expression with overall survival were examined using logistic regression. Findings: NSCLC patients showed expansion of the Tcm and Tem cell subsets among both CD4+ and CD8+ T cells compared with healthy controls. Patients with partial response to HFRT+PD-1 blockade showed reduction in Tn and expansion in TemRA cell subpopulations among CD8+ T cells and reduced PD-1+ CD4+ and PD-1+ CD8+ T cell counts, all of which were significantly correlated with overall survival. The responders to chemo-immunotherapy showed expansion of the TemRA CD4+ T cell subpopulation, decrease in Tcm CD4+ T and CD8+ T cell subpopulation. Conclusion: HFRT+PD-1 blockade and chemo-immunotherapy combination therapies induce differential memory T cell subset differentiation, offering predictive markers for treatment response. Trial Registration: ChiCTR-1900027768 Funding: This research was entirely funded by Functional study of Mir-183 in initiating cells of CD133+/CD326+ lung adenocarcinoma, 2013/01-2015/12, Project leader, Youth Fund project of National Natural Science Foundation of China； Immune mechanism of 3D guided Hypofractionation Radiotherapy in the treatment of lung adenocarcinoma， 2017/01-2019/12， Project leader， Luzhou People's Government - Southwest Medical University science and technology strategic cooperation fund；Luzhou Municipal Government and Southwest Medical University (2019LZXNYDC04);the joint project of People’s Government of Luxian County and Southwest Medical University (2019LXXNYKD-06);Joint Project of Sichuan University and Luzhou Industrial Research Institute (2020CDLZ-24). Declaration of Interest: None to declare. Ethical Approval: This prospective trial was approved by our ethics committee (No. KY2019276)