The association between monocytic myeloid-derived suppressor cells levels and the anti-tumor efficacy of anti-PD-1 therapy in NSCLC patients

Abstract

Monocytic myeloid-derived suppressor cells (M-MDSCs), granulocytic MDSC (G-MDSCs) and regulatory T cells (Tregs) inhibit adaptive anti-tumor immunity and undermine the efficacy of anti-PD-1 therapy. However, the impact of anti-PD-1 treatment on these immunosuppressive cells has not been clearly defined in non-small cell lung cancer (NSCLC). In this retrospective study, 27 advanced NSCLC patients were divided into partial response (PR), stable disease (SD), and progressive disease (PD) groups. The impact of anti-PD-1 therapy on circulating Tregs, G-MDSCs, and M-MDSCs was assessed by flow cytometer. Here, we found that anti-PD-1 treatment boosted circulating Tregs levels, which presented the most remarkable augment during the first two therapeutic cycles, in NSCLC patients. In contrast, anti-PD-1 therapy did not overall change G-MDSCs and M-MDSCs levels. However, the PR group had a higher baseline level of M-MDSCs, which exhibited a significant decrease after the first cycle of anti-PD-1 treatment. Besides, M-MDSCs levels in the PR group were maintained at a low level in the following therapeutic cycles. Consistently, Tregs levels robustly increased in the syngeneic tumor model after anti-mouse PD-1 Ab treatment. Accordingly, M-MDSCs neutralization by anti-mouse ly6c Ab enhanced the anti-tumor efficacy of anti-PD-1 therapy in mice. Finally, the decreased M-MDSCs levels were associated with the enhanced effector CD8 + T cells expansion in the PR group and mice. In conclusion, anti-PD-1 therapy upregulates Tregs levels in NSCLC patients, and the M-MDSC levels are associated with the anti-tumor efficacy of anti-PD-1 treatment. Neutralization of M-MDSCs may be a promising option to augment anti-PD-1 therapy efficacy in NSCLC.

High Levels of Circulating Monocytic Myeloid-Derived Suppressive-Like Cells Are Associated With the Primary Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: An Exploratory Analysis

“…This finding is also opposite to ours. The authors of this work sought to explain this result with a supposed effect of anti-PD-1 treatment on the decrease of M-MDSCs, but they state that “the mechanism for the decreased M-MDSCs after anti-PD-1 treatment in PR group was unknown” ( 25 ). Conversely, in another work, NSCLC patients who showed low levels of PMN-MDSCs or M-MDSCs at baseline experienced a longer PFS and a better OS, and a decrease or increase of these cells in the peripheral blood was not associated with changes in PFS and OS.…”

Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade

“…The presence of Ly6C hi myeloid cells, which were abundant in the 6TG-YummTG1.1 tumors, has previously been shown to hinder the efficacy of anti-PD1 therapy in non-small-cell lung carcinoma (NSCLC) patients. 48 Depleting Ly6C cells in a syngeneic lung adenocarcinoma mouse model improved antitumor efficacy of anti-PD1 therapy via expansion of effector CD8 T cells. 48 Furthermore, whereas anti-PD1 therapy improved tumor control in mice with 6TG-pretreated tumors, we did not observe the same effect when 6TG was administered orally to simulate a clinical context.…”

PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review

“…A strong positive correlation between the MDSC percentage and neutrophil/lymphocyte rate (NLR) (a prognostic marker in both ipilimumab and nivolumab therapy) has also been investigated in patients with breast cancer and non-small cell lung carcinoma [ 78 , 79 ] following PD-1 therapy, showing a correlation of the clinical response with decreased MDSCs or a decreased neutrophil/lymphocyte ratio. In another example, the impact of circulating Tregs, G-MDSCs, and M-MDSCs on anti-PD-1 therapy was assessed in non-small cell lung cancers by flow cytometry [ 80 ]. Anti-PD-1 treatment boosted circulating Treg levels; in contrast, anti-PD-1 therapy did not change G-MDSC and M-MDSC levels overall.…”

“…Only one small-scale study of CPI therapy in Ph (-) MPN [ 10 ] has been reported so far, in which, it was shown to be ineffective, and no clinical trial of CPI in the treatment of MPN has been listed in 2022 among the NIH clinical trials. MDSCs are considered as important to CPI therapy resistance [ 73 , 80 , 169 , 170 , 171 ]. Therefore, the failure of CPI therapy in Ph (-) MPN is most likely related to MDSCs.…”