Association of relative neutrophilia with a distinct immunoinhibitory milieu in non-small cell lung cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14047-e14047
Author(s):  
Kyle Gregory Mitchell ◽  
Lixia Diao ◽  
Hai T. Tran ◽  
Marcelo Vailati Negrao ◽  
Tatiana Karpinets ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Complete Blood Count ◽  
Lymphocyte Activation ◽  
Predictive Biomarker ◽  
Gene Signature ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

e14047 Background: Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with poor prognosis in non-small cell lung cancer (NSCLC); the biological underpinnings of this observation have not been fully elucidated. We examined the relationships between peripheral neutrophil counts (PMN), NLR, circulating cytokines and angiogenic factors (CAF), and tumor microenvironment (TME) features in NSCLC. Methods: 150 patients with resectable NSCLC were enrolled in an immunoprofiling project. A panel of 43 CAFs was used to analyze preoperative plasma samples. Chemotherapy-naïve patients with CAF and a complete blood count ≤30 days preoperatively were included (n = 66; Table). For a subset, transcriptional signatures (MCP-counter, n = 50) and flow cytometry (n = 19) were used to identify TME phenotypes. Results: Increased PMNs were associated with increased pro-inflammatory CAF such as IL-1b (r = 0.392) and IL-6 (r = 0.339), as well as Th17/Tc17 associated CAF IL-17A (r = 0.320) and TNF-a (r = 0.368). Elevated NLR was inversely correlated with the lymphocyte activation marker soluble CD27 (r = -0.320, p = 0.009). This negative association was mirrored in the TME, as tumor neutrophil signatures were inversely correlated with a local IFN-g gene signature (r = -0.626, p < 0.001). Interestingly, a Th17/Tc17 peripheral signature (elevated IL-17A) was associated with an enrichment of CD8+TIM3+ cells (r = 0.623, p = 0.042) in the tumor. While this requires confirmation in a larger cohort, this correlation provides a potential rationale for targeting TIM3 in this population. Upon analysis of clinical characteristics, peripheral PMNs and NLR were higher among patients with squamous histology (PMN p = 0.009; NLR p = 0.034) and positively correlated with tumor size (PMN r = 0.344, p = 0.004; NLR r = 0.363, p = 0.003). Conclusions: A relative neutrophilia in NSCLC patients is associated with an inflammatory milieu suggestive of a Th17/Tc17 presence and decreased lymphocyte activation that is reflected within the TME. Further investigation is needed to define the role of NLR as a predictive biomarker and to identify whether neutrophils or Th17/Tc17 T cells could serve as a therapeutic target to improve immunotherapy response in NSCLC.[Table: see text]

scholarly journals Comutations in DDR Pathways Predict Atezolizumab Response in Non-Small Cell Lung Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Anning Xiong ◽  
Wei Nie ◽  
Yan Zhou ◽  
Changhui Li ◽  
Kai Gu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Death Receptor ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

The presence of comutations (co-mut+) in DNA damage response and repair (DDR) pathways was associated with improved survival for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC). However, it remains unknown whether co-mut+ status could be a predictive biomarker for immunotherapy. We aimed to explore the predictive role of co-mut+ status in the efficacy of ICIs. A total of 853 NSCLC patients from OAK and POPLAR trials were included in the analyses for the relationship between co-mut status and clinical outcomes with atezolizumab treatment. In co-mut+ NSCLC patients, significantly prolonged progression-free survival (PFS) (p = 0.004) and overall survival (OS) (p &lt; 0.001) were observed in atezolizumab over docetaxel. The interaction between co-mut status and treatment was significant for PFS (p for interaction = 0.010) and OS (p for interaction = 0.017). In patients with negative or low programmed death receptor-ligand 1 expression, co-mut+ status still predicted improved clinical outcomes from atezolizumab therapy. These findings suggested that co-mut status may be a promising predictor of ICI therapy in NSCLC.

scholarly journals Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3828
Author(s):  
Anello Marcello Poma ◽  
Rossella Bruno ◽  
Iacopo Pietrini ◽  
Greta Alì ◽  
Giulia Pasquini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Cell ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Durable Response ◽  
Nsclc Patients

Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.

scholarly journals Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB2 harmonization project comparing three NGS panels

2021 ◽  
Vol 9 (5) ◽  
pp. e001904
Author(s):  
Javier Ramos-Paradas ◽  
Susana Hernández-Prieto ◽  
David Lora ◽  
Elena Sanchez ◽  
Aranzazu Rosado ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Value ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Reproducibility Study ◽  
Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.MethodsWe evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.ResultsBoth panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.ConclusionsBoth panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

scholarly journals Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1794
Author(s):  
Alice Indini ◽  
Erika Rijavec ◽  
Francesco Grossi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Circulating Biomarkers ◽  
Small Cell Lung ◽  
Nsclc Patients

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.

Sign in / Sign up

Export Citation Format

Share Document