Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

By Nicholas McGranahan, A. Furness, R. Rosenthal, S. Ramskov, R. Lyngaa, S. Saini, M. Jamal-Hanjani, G. Wilson, Nicolai J. Birkbak, C. Hiley and 26 more. Science, 2016

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The cellular ancestry of tumor antigens One contributing factor in antitumor immunity is the repertoire of neoantigens created by genetic mutations within tumor cells. Like the corresponding mutations, these neoantigens show intratumoral heterogeneity. Some are present in all tumor cells (clonal), and others are present in only a fraction of cells (subclonal). In a study of lung cancer and melanoma, McGranahan et al. found that a high burden of clonal tumor neoantigens correlated with improved patient survival, an increased presence of tumor-infiltrating lymphocytes, and a durable response to immunotherapy. Science, this issue p. 1463 Analysis of the cellular ancestry of tumor neoantigens can predict which are most likely to induce an immune response. As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/573646106a647e2f4b18ca3e430401ac86f8097c

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Citations in the corpus

Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer (2016, background): “Although clonal neoantigens have recently been reported to drive anti-tumor responses to checkpoint inhibitors (34), our analyses suggest that underlying immune responses target both truncal and”
The Immune Landscape of Cancer (2018, background): “However, the biology of the immune microenvironment driving these responses is incompletely understood (Hugo et al., 2016; McGranahan et al., 2016) but is critical to the design of immunotherapy treatment strategies.”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “…and recent data in both experimental models and patients show that tumors with high subclonal ITH are less likely to respond to immune checkpoint inhibitors than more homogeneous tumors (Anagnostou et al., 2017; Gejman et al., 2018; McGranahan et al., 2016; Milo et al., 2018; Wolf et al., 2019).”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “PD-L1 expression, tumor mutational burden, tumor infiltrating lymphocytes (TILs) or related gene expression signatures have been explored as potential predictors and various other markers are currently under investigation (Chen et al., 2016; Cristescu et al., 2018; Garon et al., 2015; Hugo et al., 2”
Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features (2017, neutral): “Variable Training set (n=225) Validation Set (n=131) TCGA set (n=190) Median age (IQR) 66 (61-72) 66 (55-71) 62 (52-70) Gender, male (%) 178 (79) 96 (73) 123 (65) Etiology (%) Hepatitis C 101 (46) 64 (50) N/A Hepatitis B 48 (21) 39 (30) N/A Alcohol 33 (15) 6 (5) N/A Others 38 (17) 19 (15) Child-Pugh”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “, 2015), as well as distinct CCNE1 amplifications in ovarian cancers (McPherson et al., 2016).”
Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures (2016, background): “Others have suggested that the clonality of neo-antigens may drive immune recognition [59] and we consistently observed an inverse correlation between intratumor heterogeneity and immune infiltration in multiple datasets.”