Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Yu, Hui; Chen, Zhengming; Ballman, Karla V.; Watson, Mark A.; Govindan, Ramaswamy; Lanc, Irena; Beer, David G.; Bueno, Raphael; Chirieac, Lucian R.; Chui, M. Herman; Chen, Guoan; Franklin, Wilbur A.; Gandara, David R.; Genova, Carlo; Brovsky, Kristine; Joshi, Mary Beth; Merrick, Daniel T.; Richards, William G.; Rivard, Christopher J.; Harpole, David H.; Tsao, Ming‐Sound; Bokhoven, Adrie van; Shepherd, Frances A.; Hirsch, Fred R.

doi:10.1016/j.jtho.2018.09.006

Cited by 75 publications

(69 citation statements)

References 52 publications

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“…The PD-L1 expression level appeared to be a persuasive marker because PD-L1-positive lesions were more vulnerable to PD-1 inhibition therapy than PD-L1-negative lesions, yet clinical survival data did not show a significant relationship. [414][415][416][417] The predictive role of PD-L1 expression in CRC is considered to be limited because in pMMR CRC, no obvious trend was observed between PD-L1 expression levels and drug efficacy. 382,387 A high mutational burden correlates with elevated levels of neoantigens.…”

Section: Immune Checkpoint Inhibitor Therapymentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

1,130

821

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Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.

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Section: Immune Checkpoint Inhibitor Therapymentioning

confidence: 99%

Comprehensive review of targeted therapy for colorectal cancer

Xie

Chen

Fang

2020

Sig Transduct Target Ther

1,130

821

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“…Moreover, although PD-L1 plays an important immunosuppressive role in tumor development, the prognostic effect of tumor PD-L1 has not been consistent in previous studies. [33][34][35][36][37][38][39][40][41] One of the possible reasons was speculated that tumor PD-L1 may affect the prognosis by altering macrophage function. Therefore, PD-L1 and macrophages together may affect the prognosis of cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Cao

Che

Qiu

et al. 2019

CMAR

101

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These authors contributed equally to this workBackground: Lung cancer is the leading cause of cancer-related death worldwide. Although the macrophages can affect the development of tumor, the contribution of macrophages to the prognosis of non-small-cell lung cancer (NSCLC) is still controversial. Moreover, anti-PD-1 therapy can redirect macrophages from an M2 to an M1 phenotype, suggesting that tumor PD-L1 may affect the prognostic role of macrophages. Therefore, in this study, we aimed to display a macrophage landscape to clarify the function of macrophages, considering the localization and polarization of the macrophages, and evaluate the effect of M2 macrophages and tumor PD-L1 in combination on the prognosis of NSCLC. Methods: We performed multiplex quantitative immunofluorescence staining of pan-cytokeratin (CK), CD68, CD163, PD-L1, and DAPI on one tissue specimen simultaneously from 137 NSCLC patients. Results: M2 macrophages, involved marginM2 (M2 macrophages in tumor stroma), and centralM2 (M2 macrophages infiltrating into tumor islets) increased as the tumor stage increased. More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers. Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages. Moreover, patients with centralM2 less PD-L1 − tumors showed the best OS and DFS, while the patients with centralM2 more PD-L1 + tumors showed the worst OS and DFS, and the two groups with centralM2 less PD-L1 + and centralM2 more PD-L1 − were in the middle (P=0.002, 0.034, respectively). Conclusion: Tumor islet-infiltrating M2 macrophages influence the prognosis of NSCLC patients. The analysis of M2 macrophages and tumor PD-L1 in combination may enhance the accuracy of prognostic prediction. This study provides a new understanding of macrophages in the development of NSCLC through the analysis of macrophage landscape.

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“…However, only a subset of patients responds to ICIs, and PD-L1 expression exhibits limited efficacy as a predictive biomarker (7). More recently, a high tumor mutational burden (TMB), as a surrogate for immunogenic tumor neoantigen presentation (8), was associated with a favorable response to ICIs in patients with NSCLC irrespective of PD-L1 expression in both tissue and plasma samples (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study

Boeri

Milione

Proto

et al. 2019

Clinical Cancer Research

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Purpose: Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non-small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients with advanced NSCLC treated with ICIs. Experimental Design: The MSC risk level was prospectively assessed in a consecutive series of 140 patients with NSCLC before starting treatment with ICIs. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in strata of PD-L1 and MSC alone or combined were considered as endpoints. Multiple plasma samples to monitor MSC risk level during treatment were also profiled. Results: Adequate tissue and plasma samples were available from 111 (79%) and 104 (75%) patients with NSCLC, respectively. MSC risk level was associated with ORR (P ¼ 0.0009), PFS [multivariate HR ¼ 0.31; 95% confidence interval (CI), 0.17-0.56; P ¼ 0.0001], and OS (multivariate HR ¼ 0.33; 95% CI, 0.18-0.59; P ¼ 0.0002). The combination of MSC and PD-L1 stratified patients into three risk groups having 39%-18%-0% 1-year PFS (P < 0.0001) and 88%-44%-0% 1-year OS (P < 0.0001), according to the presence of 2-1-0 favorable markers. During treatment, MSC risk level decreased or remained low until tumor progression in patients with responsive or stable disease. Conclusions: The plasma MSC test could supplement PD-L1 tumor expression to identify a subgroup of patients with advanced lung cancer with worse ORR, PFS, and OS in immunotherapy regimens.

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Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Cited by 75 publications

References 52 publications

Comprehensive review of targeted therapy for colorectal cancer

Comprehensive review of targeted therapy for colorectal cancer

<p>M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer</p>

Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study

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