Circulating regulatory T cells predict efficacy and atypical responses in lung cancer patients treated with PD-1/PD-L1 inhibitors

Abstract

Background Immune checkpoint inhibitors (ICIs) have become the standard of care for a variety of cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the frequency of pseudoprogression and hyperprogression in lung cancer patients treated with ICIs in the real world and aimed to discover a novel candidate marker to distinguish pseudoprogression from hyperprogression soon after ICI treatment. Methods This study included 74 patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors at Chungnam National University Hospital (CNUH) between January 2018 and August 2020. Chest X-rays were examined on day 7 after the first ICI dose to identify changes in the primary mass, and the response was assessed by computed tomography (CT). We evaluated circulating regulatory T (Treg) cells using flow cytometry and correlated the findings with clinical outcomes. Results The incidence of pseudoprogression was 13.5%, and that of hyperprogression was 8.1%. On day 7 after initiation of treatment, the frequency of CD4+CD25+CD127loFoxP3+ Treg cells was significantly decreased compared with baseline (P = 0.038) in patients who experienced pseudoprogression and significantly increased compared with baseline (P = 0.024) in patients who experienced hyperprogression. In the responder group, the frequencies of CD4+CD25+CD127loFoxP3+ Treg cells and PD-1+CD4+CD25+CD127loFoxP3+ Treg cells were significantly decreased 7 days after commencement of treatment compared with baseline (P = 0.034 and P < 0.001, respectively). Conclusion Circulating Treg cells represent a promising potential dynamic biomarker to predict efficacy and differentiate atypical responses, including pseudoprogression and hyperprogression, after immunotherapy in patients with NSCLC.

The efficient circulating immunoscore predicts prognosis of patients with advanced gastrointestinal cancer

“…IS and TB scoring systems of metastatic focus constructed by Wang ) also revealed good independent predictive values [22,24]. At present, increasing studies on the exploratory analysis of immune cell subtypes in peripheral blood, regarding its prognostic value, indicated that expression levels of circulating regulatory T cells, NK cells, CD3 + T cells, CD4 + T cells, and CD8 + T cells were also significantly linked to survival [33][34][35][36]. Although the above immune score concerning TME demonstrates good predictive function, its evaluation process remains very complex, limiting its extensive application in clinic.…”

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

“…Although no clinicopathological variables of HPD were reported in the study, in the exploratory biomarker analysis of peripheral blood, CD8 + T lymphocytes, lower effector/memory subsets (CCR7 - CD45RA - T cells in total CD8 + T cells), and higher populations of severely depleted cells (TIGIT + T cells in PD-1 + CD8 + T cells) were associated with HPD and poor survival. In two real-world studies, the incidence of HPD in advanced NSCLC was 19.2% (16/83) [ 24 ] and 8.1% (6/74) [ 25 ] . Among them, one study reported an increased rate of fluid accumulation (up to 90%) and decreased albumin level, while the other showed a significant increase in the number of circulating Treg cells in HPD patients.…”

“…Kang et al . [ 25 ] found significantly higher FoxP3 + Treg cells in 74 patients with advanced NSCLC who developed HPD and significantly fewer Treg cells in non-HPD patients ( P = 0.024). Therefore, PD-1 + Treg cells could be an effective biomarker for the identification of HPD [ 64 ] .…”

Current Understanding and Future Perspectives on Hyperprogressive Disease Highlight the Tumor Microenvironment

“…Research has indicated that PD‐1 inhibitors can facilitate the proliferation of highly suppressive PD‐1 + effector Treg cells and enhance their participation in the immunosuppressive process in patients with advanced gastric cancer treated with PD‐1 monoclonal antibody 88 . In patients with NSCLC who experienced HPD, Treg cell frequency significantly increased on day 7 compared with baseline ( P = .024) 89 …”

“…88 In patients with NSCLC who experienced HPD, Treg cell frequency significantly increased on day 7 compared with baseline (P = .024). 89 T Cells. Kim et al used classical markers (CCR7 and CD45RA) to analyze the frequency of effector/memory T cells in peripheral blood to detect pre-established antitumor immunity.…”