Research Article

Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy

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Science  12 Oct 2018:
Vol. 362, Issue 6411, eaar3593
DOI: 10.1126/science.aar3593

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Mining immunotherapy clinical trials

Clinical trial data can provide a wealth of information about how drugs work. Yet such information often belongs to pharmaceutical companies and is rarely accessible to the scientific community at large. Cristescu et al. provide exploratory analysis of a cancer genomics dataset, collected from four separate clinical trials of Merck's PD-1 immunotherapy drug, pembrolizumab. This informative public resource examines more than 300 patient samples representing 22 different tumor types. Two widely used signatures that currently predict immunotherapy response are tumor mutational burden and a “hot” T cell–inflamed microenvironment. The study analyzed these two proposed biomarkers in combination to see what predictive clinical utility they may hold.

Science, this issue p. eaar3593

Structured Abstract


Immunotherapy targeting the programmed cell death protein–1 (PD-1) axis elicits durable antitumor responses in multiple cancer types. However, clinical responses vary, and biomarkers predictive of response may help to identify patients who will derive the greatest therapeutic benefit. Clinically validated biomarkers predictive of response to the anti–PD-1 monoclonal antibody pembrolizumab include PD-1 ligand 1 (PD-L1) expression in specific cancers and high microsatellite instability (MSI-H) regardless of tumor type. Tumor mutational burden (TMB) and T cell–inflamed gene expression profile (GEP) are emerging predictive biomarkers for pembrolizumab. Both PD-L1 and GEP are inflammatory biomarkers indicative of a T cell–inflamed tumor microenvironment (TME), whereas TMB and MSI-H are indirect measures of tumor antigenicity generated by somatic tumor mutations. However, the relationship between these two categories of biomarkers is not well characterized.


This study assessed the potential for TMB and a T cell–inflamed GEP to jointly predict clinical response to pembrolizumab in >300 patient samples with advanced solid tumors and melanoma across 22 tumor types from four KEYNOTE clinical trials. To assess the individual and joint clinical utility of TMB and GEP, patients were stratified in four biomarker-defined clinical response groups [GEP low and TMB low (GEPlo TMBlo), GEP low and TMB high (GEPlo TMBhi), GEPhi TMBlo, and GEPhi TMBhi] based on predefined cutoffs for TMB and GEP. These patient-defined biomarker groups were further used to guide transcriptome and exome analyses of tumors in a large molecular database [The Cancer Genome Atlas (TCGA)] (n = 6384 tumors) to identify targetable patterns of biology that may modulate response and resistance.


TMB and GEP exhibited only modest correlation and were independently predictive of response across the KEYNOTE clinical datasets. We found that objective response rates were strongest in patients with GEPhi TMBhi (37 to 57%), moderate in those with GEPhi TMBlo (12 to 35%) and GEPlo TMBhi (11 to 42%), and reduced or absent in those with GEPlo TMBlo (0 to 9%) (see the figure). Additionally, longer progression-free survival times were seen in patients with higher levels of both TMB and GEP. Findings were comparable when TMB and PD-L1 expression were jointly assessed. Within TCGA database, GEP and TMB again had a low correlation, demonstrating the potential to jointly stratify transcriptomic and genomic features across cancer types. Specific gene expression patterns reflective of TME biology showed significant associations with TMB, GEP, or both. In particular, gene set enrichment analysis identified proliferative and stromal, myeloid, and vascular biology corresponding to specific TMB-defined subgroups within GEPhi tumors. In TMBhi tumors, indication-dependent somatic DNA alterations in key cancer driver genes showed a strong negative association with GEP.


This analysis shows that TMB and inflammatory biomarkers (T cell–inflamed GEP and PD-L1 expression) can jointly stratify human cancers into groups with different clinical responses to pembrolizumab monotherapy and identify patterns of underlying, targetable biology related to these groups. TMB and inflammatory biomarkers independently predict response and may capture distinct features of neoantigenicity and T cell activation, respectively. This approach may provide a precision medicine framework for rationally constructing and evaluating anti–PD-1– and/or –PD-L1–based combination therapy regimens.

Biomarker-defined responses to pembrolizumab monotherapy identify targetable-resistance biology.

(A) Tumors have low TMB and low neoantigenicity and lack a T cell–inflamed TME. (B) Tumors can evade the immune response despite high TMB and high neoantigenicity. (C) Although T cells are present, stromal and/or endothelial factors in the TME, low TMB, and low neoantigenicity impede their activity. (D) Tumors have high TMB, high neoantigenicity, and a T cell–inflamed TME, typified by activated T cells and other immune cells with cytolytic roles.


Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.

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