Myeloid immunosuppressive state as a predictor of rapidly progressive phenotype and poor survival in advanced non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 inhibitors.

Abstract

e20594 Background: Immune subpopulations within the tumor microenvironment (TME) play a central role in determining response to checkpoint inhibitors. Myeloid derived suppressor cells, a heterogeneous population of immature myeloid cells, have a predominantly immunosuppressive role by stimulating T regulatory cells. We hypothesize that elevated myeloid-to-lymphocyte measures in the peripheral blood predict for greater numbers of myeloid derived suppressor cells in the TME and worse outcomes. Methods: In advanced NSCLC patients who received immunotherapy between 2010-2018, baseline characteristics collected retrospectively included age, sex, histology, stage, smoking status, ethnicity, PD-L1 expression and tumor genotype. Pre-treatment neutrophil/lymphocyte (NLR) and monocyte/lymphocyte ratios (MLR) were log transformed and analyzed using cox and logistic regression models. Results: Among 219 eligible patients, a high NLR was associated with shorter time-to-treatment-failure (HR 1.38, 95%CI 1.09-1.75, p = 0.008) and poorer OS (HR 1.62, 95%CI 1.23-2.14, p < 0.001), independent of PD-L1 levels. Disproportionate increases in NLR and MLR were highly correlated (Spearman’s rho = 0.78). Further, higher NLR (p = 0.09) or MLR (p = 0.06) tended to associate with best overall response (BOR) to immunotherapy, with higher rates of progressive disease (PD) and lower rates of clinical response. A high NLR (p = 0.01) and MLR (p = 0.02) were associated with a rapidly progressive phenotype defined by PD as the BOR and duration of therapy ≤2 months. This remained significant after adjusting for confounders in a multivariate model (p = 0.03 for NLR and p = 0.03 for MLR). No associations were observed between high myeloid counts and other clinical prognostic factors such as liver metastases. Conclusions: A myeloid immunosuppressive state characterized by a disproportionate increase in peripheral immune myeloid populations is significantly associated with primary refractory disease, rapidly progressive phenotype, and poorer survival. Further investigation into myeloid mediated mechanisms of resistance is warranted.