Intratumoral heterogeneity as a predictive biomarker in anti-PD-(L)1 therapies for non-small cell lung cancer

Fang, Wenfeng; Jin, Haoxuan; Zhou, Huaqiang; Hong, Shaodong; Ma, Yuxiang; Zhang, Yaxiong; Su, Xiaofan; Chen, Longyun; Yang, Yunpeng; Xu, Shengqiang; Liao, Yuwei; He, Yuming; Zhao, Hongyun; Huang, Yan; Gao, Zhibo; Zhang, Li

doi:10.1186/s12943-021-01331-9

Cited by 44 publications

(39 citation statements)

References 8 publications

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“…Intratumoral heterogeneity (ITH) refers to spatial or temporal heterogeneity with respect to the distribution of genomic diversity in a single tumor, resulting from cumulative gene mutations. Patients with low ITH were found to perform better in presentation and recognition of neoantigens during immunotherapy, predicting the prognosis in NSCLC ( 25 ). The research indicated that the response to immunotherapy can be optimally predicted by using the combination of ITH and TMB, and subsequently verified a consistent role of ITH in esophageal and GC.…”

Section: Biomarkers Of Ici Therapeutic Efficacy Against Digestive Sys...mentioning

confidence: 99%

Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers

Wang

et al. 2022

Front. Immunol.

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Immunotherapy represented by immune checkpoint inhibitors has gradually entered a new era of precision medicine. In view of the limited clinical benefits of immunotherapy in patients with digestive system cancers, as well as the side-effects and high treatment costs, development of biomarkers to predict the efficacy of immune therapy is a key imperative. In this article, we review the available evidence of the value of microsatellite mismatch repair, tumor mutation burden, specific mutated genes or pathways, PD-L1 expression, immune-related adverse reactions, blood biomarkers, and patient-related biomarkers in predicting the efficacy of immunotherapy against digestive system cancers. Establishment of dynamic personalized prediction models based on multiple biomarkers is a promising area for future research.

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Section: Biomarkers Of Ici Therapeutic Efficacy Against Digestive Sys...mentioning

confidence: 99%

Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers

Wang

et al. 2022

Front. Immunol.

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“…Sensitivity to immunotherapies can vary significantly depending on the heterogeneity of neoantigens and machinery of antigen presentation or cytotoxic signaling pathways [ 94 , 95 ]. In a cohort of patients with metastatic NSCLC (discovery) or other solid tumor types (validation), higher intratumoral heterogeneity of mutations/neoantigens showed independent or joint (with mutational burden), predictive significance to poorer survival outcomes [ 96 ]. Experimental models also provide convincing evidence for the predictive value of immunological heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of the tumor immune microenvironment and its clinical relevance

et al. 2022

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During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies.

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“…And pathway-model with MATH is the most stable model compared to other models and single factor variables. A recent study has shown that the integration of TMB and MATH forms a predictive marker for the response of ICIs treatment in melanoma (16), and another study has also revealed that intratumoral heterogeneity (MATH is an indicator of intratumoral heterogeneity) can be used as a biomarker to predict the response of ICIs treatment in NSCLC (15). Moreover, we found that the common biomarkers were not significant correlation according to the Pearson correlation coefficient, and the accuracy of each single-factor variable was lower than the pathway-model or tri-model.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with a higher TMB or higher PD-L1 expression have a higher likelihood of immunotherapy response. Another novel statistical value, mutant-allele tumor heterogeneity (MATH), has been documented that is not only as a measure of intratumor genetic heterogeneity but also can be used as a biomarker to predict the response of treatment for patients (13)(14)(15)(16)). In addition, recent studies have shown that some pathways, such as IFN-gamma, NF-kb, and Wnt, are cancer-related immune-regulation pathway, which may be potential indicators to explore the effect of immunotherapy (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer

Jiang

Zheng²,

Zhang³

et al. 2021

Front. Immunol.

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BackgroundThe development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immune-oncology. However, the low response rate is the major problem of ICI treatment. The recent studies showed that response rate to single-agent programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibition in unselected non-small cell lung cancer (NSCLC) patients is 25% so that researchers defined several biomarkers to predict the response of immunotherapy in ICIs treatment. Common biomarkers like tumor mutational burden (TMB) and PD-L1 expression have several limitations, such as low accuracy and inadequately validated cutoff value.MethodsTwo published and an unpublished ICIs treatment NSCLC cohorts with 129 patients were collected and divided into a training cohort (n = 53), a validation cohort (n = 22), and two independent test cohorts (n = 34 and n = 20). We identified six immune-related pathways whose mutational status was significantly associated with overall survival after ICIs treatment. Then these pathways mutational status combined with TMB, PD-L1 expression and intratumor heterogeneity were incorporated to build a Bayesian-regularization neural networks (BRNN) model to predict the ICIs treatment response.ResultsWe firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers. The survival analysis of six immune-related pathways revealed the mutational status could distinguish overall survival after ICIs treatment. When predicting immunotherapy efficacy, the overall accuracy of area under curve (AUC) in validation cohort reaches 0.85, outperforming previous predictors in either sensitivity or specificity. And the AUC in two independent test cohorts reach 0.74 and 0.80.ConclusionWe developed a pathway-model that could predict the efficacy of ICIs in NSCLC patients. Our study made a significant contribution to solving the low prediction accuracy of immunotherapy of single biomarker. With the accumulation of larger data sets, further studies are warranted to refine the predictive performance of the approach.

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Intratumoral heterogeneity as a predictive biomarker in anti-PD-(L)1 therapies for non-small cell lung cancer

Cited by 44 publications

References 8 publications

Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers

Research Progress of Biomarkers for Immune Checkpoint Inhibitors on Digestive System Cancers

Heterogeneity of the tumor immune microenvironment and its clinical relevance

Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer

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