STING Pathway Expression Identifies NSCLC With an Immune-Responsive Phenotype

Abstract

Introduction: Although the combination of antiprogrammed cell death-1 or anti-programmed cell death ligand-1 (PD-L1) with platinum chemotherapy is a standard of care for NSCLC, clinical responses vary. Even though predictive biomarkers (which include PD-L1 expression, tumor mutational burden, and inflamed immune microenvironment) are validated for immunotherapy, their relevance to chemoimmunotherapy combinations is less clear. We have recently reported that activation of the stimulator of interferon genes (STING) innate immune pathway enhances immunotherapy response in SCLC. Here, we hypothesize that STING pathway activation may predict and underlie predictive correlates of antitumor immunity in NSCLC.Methods: We analyzed transcriptomic and proteomic profiles in two NSCLC cohorts from our institution (treatmentnaive patients in the Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax study and relapsed patients in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination study) and The Cancer Genome Atlas (N ¼ 1320). Tumors were stratified by STING activation on the basis of protein or mRNA expression of cyclic GMP-AMP synthase, phospho-STING, and STING-mediated

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

“…These results suggest new therapeutic targets and drug combinations for SCLC treatment which may be beneficial for specific epigenetic tumor landscapes. Some of the newly discovered associations, e.g., those for TREX1, may suggest potential novel direct drug targets in tumors with residual TREX1 expression, and also add to the accumulating body of evidence about the importance of upregulation of the cGAS/STING pathway in treatment of cancer patients [79,80,85]. Similarly, other associations reported in our study may suggest novel therapy targets, indicate potential broader molecular pathways of interest, and provide biomarkers for patient stratification.…”

Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer

“…Furthermore, the genomic profiling of these three tumours underline the hypothesis that alterations in DDR genes could promote the interplay between innate and adaptive immunity involved in response to ADCC inducing immunotherapy. 17 Furthermore, in this report we also provide evidence that the combination of cetuximab plus avelumab induces NK cell-driven ADCC in patients that were enrolled in the CAVE-Lung trial. Induction in ADCC may be monitored during therapy and it could represent a potential biomarker of response.…”

“…According to our previous publication, presence of STK11/TP53 co-mutation and DDR alterations defines a subgroup of NSCLC with features of immune responsiveness. 17 Ex vivo evidence of NK activation in NSCLC patients treated with avelumab plus cetuximab in the CAVE-Lung trial and its correlation with antitumour activity In order to study the potential induction of ADCC following treatment with avelumab plus cetuximab, NK cells were isolated from PBMCs from patients enrolled in the CAVE-Lung study. LDH release assay was performed on human H1299 lung cancer cells as target cells, which were cocultured with NK cells, that were isolated from PBMCs of five responding patients.…”

Analyses of DNA methylation involved in the activation of nuclear karyopherin alpha 2 leading to the progression and prognostic significance across human breast cancer

“…Somatically acquired inherited, epigenetic, transcriptomic, and proteomic alterations are the major alterations occur in specific genomic regions, which could lead inhibitory or carcinogenic roles [32][33][34]. Therefore, the frequencies of alterations and mutations in KPNA2 were analyzed using the COSMIC and cBioPortal databases.…”

“…2B). 33.33% C > T, 33.33% G > A, and 16.67% G > T. As determined using cBioPortal, the KPNA2 mutation frequency was less than 1.5% in patients with breast cancer. (Fig.…”