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Abstract
Background Emerging data suggest poor outcome to anti- PD(L)1 blocking agents in patients with STK11mut tumors1. In the current study, we undertook in-depth translational evaluations of three Ph1/Ph2 independent studies of Durvalumab ± Tremelimumab to elucidate the biology associated with STK11 mutations leading to reduced clinical response in patients with non-squamous NSCLC.
Methods Mutational status was evaluated by ctDNA or Foundation One CDx as previously described1. RNA sequencing was conducted on baseline frozen biopsies (N=70). Selected proteins (N=66) were measured by Myriad RBM multiplexed immunoassays on baseline serum (n=91). Screening and longitudinal whole blood was assessed for circulating quantities of T, B or NK cells and activated or memory T cell subsets using bioanalytically-validated, flow cytometry-based immunophenotyping assays. Exploratory analyses of translational endpoints according to STK11 mutational status were conducted by Wilcoxon rank-sum test.
Results In the periphery, a reduced number (> 2-fold decreased in median quantities) of NK cells, CD4+ effector memory, CD4+ HLA-DR+, CD8+ effector memory and CD8+ HLA-DR+ T cells was observed at baseline and following treatments in patients with STK11mut vs. STK11wt tumors. At baseline, increased levels of IL6 (p=0.002) and the neutrophil-attracting cytokine IL8 (p=0.02) were found in serum of patients with STK11mut tumors. In the tumor microenvironment, significantly increased expression (p< 0.05; fold change > 2) of markers associated with neutrophils, (i.e. CXCL2, IL6, CSF3), Th17 contexture (i.e. IL17A) and immune checkpoints (i.e. KIRs, PD-L1) was found in STK11mut vs. STK11wt tumors.
Conclusions The poor outcomes to immunotherapy observed in NSCLC patients with STK11mut tumors might be determined by a compromised peripheral and intra-tumoral immune phenotype. These results might help the development of novel therapeutic interventions able to unleash response to immune checkpoints in NSCLC patients harboring STK11 mutations.
Trial Registration NCT01693562, NCT02087423, NCT02000947
Reference
Jure Kunkel Met al, JCO. 2018.36.15_suppl.3028.
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