Cited by 1,192Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesCancer Genomics and Diagnostics

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

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Jardim, Denis L., Goodman, Aaron, de Melo Gagliato, Debora, Kurzrock, Razelle·2021·Cancer Cell

DOI 10.1016/j.ccell.2020.10.001PMC PMC7878292

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Abstract

Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.

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“Nevertheless, there are several challenges for the clinical implementation of TMB, especially in standardizing detection methods and appropriate thresholds by tumor type (30, 31).”
Impact of nanoparticles on immune cells and their potential applications in cancer immunotherapy
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“Higher TMB results in more neoantigens, increased T cell recognition, and better ICI therapy outcomes (Jardim et al., 2021).”
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Comprehensive Analysis Reveals Distinct Immunological and Prognostic Characteristics of CD276/B7-H3 in Pan-Cancer
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“At the molecular level, TMB is associated with deficient mismatch repair (dMMR), high microsatellite instability (MSI-H), and mutations in DNA polymerase correction domains encoding POLE and POLD1 genes (Jardim et al., 2021).”
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PD-L1 gene amplification and focality: relationship with protein expression
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An immune indicator based on BTK and DPEP2 identifies hot and cold tumors and clinical treatment outcomes in lung adenocarcinoma
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A risk score combining co-expression modules related to myeloid cells and alternative splicing associates with response to PD-1/PD-L1 blockade in non-small cell lung cancer
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Assessing the role of colonic and other anatomical sites uptake by [18F] FDG ‐PET/ CT and immune‐inflammatory peripheral blood indexes in patients with advanced non‐small cell lung cancer treated with first‐line immune checkpoint inhibitors
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A cuproptosis-related lncRNA signature for predicting prognosis and immunotherapy response of lung adenocarcinoma
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Knockdown of ADAM8 inhibits the proliferation, migration, invasion, and tumorigenesis of renal clear cell carcinoma cells to enhance the immunotherapy efficacy
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Detection of mutation profiles and tumor mutation burden of cerebrospinal fluid circulating DNA by a cancer genomic panel sequencing in glioma patients
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Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade
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Comprehensive Analysis of Prognosis and Immune Landscapes Based on Lipid-Metabolism- and Ferroptosis-Associated Signature in Uterine Corpus Endometrial Carcinoma
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Recombinant Human Adenovirus Type 5 (H101) Intra-Tumor Therapy in Patients with Persistent, Recurrent, or Metastatic Cervical Cancer: Genomic Profiling Relating to Clinical Efficacy
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“Most importantly, the methods above are invasive, relying heavily on biopsy, which further limits their utility (13, 14).”
BackgroundMethod
Computed Tomography‐Based Radiomics and Genomics Analyses for Survival Prediction of Stage III Unresectable Non‐Small Cell Lung Cancer Treated With Definitive Chemoradiotherapy and Immunotherapy
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Authors: Jardim, D. L., Goodman, A., de Melo Gagliato, D., & Kurzrock, R.
Affiliations: Hospital Sírio-Libanês (BR)
University of California San Diego (US)
Corresponding author: Kurzrock, Razelle
ORCID: Jardim, Denis L.
Goodman, Aaron
Kurzrock, Razelle
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2021-02
Volume: 39
Issue: 2
Pages: 154-173
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2020.10.001
PMC: PMC7878292
OpenAlex: W3097803258
Cited by: 1,192
References: 151
Citations by year: 2026: 134 · 2025: 263 · 2024: 294 · 2023: 276 · 2022: 171 · 2021: 53
FWCI: 13.60
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Astellas Pharma US
National Cancer Institute (P30 CA023100)
Janssen Pharmaceuticals
AstraZeneca
Bristol-Myers Squibb
Genentech
Roche
EMD Serono
Pfizer
Meso Scale Diagnostics
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: tumor mutational burden, immunotherapy biomarkers, immune checkpoint inhibitors, neoantigens, MHC class I antigen presentation, T cell receptor repertoire, cancer immunotherapy response prediction
MeSH terms: Immune Checkpoint Inhibitors, Humans, Immunotherapy, Major Histocompatibility Complex, Mutation, Neoplasms, T-Lymphocytes, Biomarkers, Tumor

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

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