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Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

ABSTRACT: Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy?=?0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.

SUBMITTER: Hwang S

PROVIDER: S-EPMC6971301 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

Hwang Sohyun S Kwon Ah-Young AY Jeong Ju-Yeon JY Kim Sewha S Kang Haeyoun H Park Joonsuk J Kim Joo-Hang JH Han Ok Jin OJ Lim Sun Min SM An Hee Jung HJ

Scientific reports 20200120 1

Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were chara ...[more]

PMID: 31959763

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Project description:BACKGROUND: Improved methods are needed for predicting prognosis and the benefit of delivering adjuvant chemotherapy (ACT) in patients with non-small-cell lung cancer (NSCLC). METHODS: A novel prognostic algorithm was identified using genomic profiles from 332 stage I-III adenocarcinomas and independently validated on a separate series of 264 patients with stage I-II tumors, compiled from five previous studies. The prognostic algorithm was used to interrogate genomic data from a series of patients treated with adjuvant chemotherapy. Those genes associated with outcome in the adjuvant treatment setting, independent to prognosis were used to train an algorithm able to classify a patient as either a responder or non-responder to ACT. The performance of this signature was independently validated on a separate series of genomic profiles from patients enrolled in a randomized controlled trial of cisplatin/vinorelbine vs. observation alone (JBR.10). RESULTS: NSCLC patients exhibiting the high-risk, poor-prognosis form of the 160-gene prognosis signature experienced a 2.80-times higher rate of 5-year disease specific death (log rank P?<?0.0001) compared to those with the low-risk, good prognosis profile, adjusted for covariates. The prognosis signature was found to especially accurate at identifying early stage patients at risk of disease specific death within 24?months of diagnosis when compared to traditional methods of outcome prediction.Separately, NSCLC patients with the 37-gene ACT-response signature (n?=?70, 64?%), benefited significantly from cisplatin/vinorelbine (adjusted HR: 0.23, P?=?0.0032). For those patients predicted to be responders, receiving this form of ACT conferred a 25?% improvement in the probability of 5-year-survival, compared to observation alone and adjusted for covariates. Conversely, in those patients predicted to be non-responders, ACT was observed to offer no significant survival benefit (adjusted HR: 0.55, P?=?0.32).The two gene signatures overlap by one gene only SPSB3, which interacts with the oncogene MET. In this study, higher levels of SPSB3 which were associated with favorable prognosis and benefit from ACT. CONCLUSIONS: These complimentary prognostic and predictive gene signatures may assist physicians in their management and treatment of patients with early stage lung cancer.

Dataset Information

Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

Publications

Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

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