The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

• Published in: Cancer cell Vol. 39; no. 2; pp. 154 - 173
• Main Authors: Jardim, Denis L., Goodman, Aaron, de Melo Gagliato, Debora, Kurzrock, Razelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.02.2021
• Subjects: biomarker; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; cancer therapy; genetics; Humans; Immune Checkpoint Inhibitors - pharmacology; immunotherapy; Immunotherapy - methods; Major Histocompatibility Complex - genetics; Major Histocompatibility Complex - immunology; Mutation - genetics; Mutation - immunology; mutattional load; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; T-Lymphocytes - immunology; cancer therapy; mutattional load; genetics; biomarker; immunotherapy
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2020.10.001

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. 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.