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

Nicholas McGranahan; Andrew J S Furness; Rachel Rosenthal; Sofie Ramskov Andersen; Rikke Birgitte Lyngaa; Sunil Kumar Saini; Mariam Jamal-Hanjani; Gareth A Wilson; Nicolai J. Birkbak; Crispin T Hiley; Thomas B K Watkins; Seema Shafi; Nirupa Murugaesu; Richard Mitter; Ayse U Akarca; Joseph Linares; Teresa Marafioti; Jake Y Henry; Eliezer M Van Allen; Diana Miao; Bastian Schilling; Dirk Schadendorf; Levi A Garraway; Vladimir Makarov; Naiyer A Rizvi; Alexandra Snyder; Matthew D Hellmann; Taha Merghoub; Jedd D Wolchok; Sachet A Shukla; Catherine J Wu; Karl S Peggs; Timothy A Chan; Sine Reker Hadrup; Sergio A Quezada; Charles Swanton

doi:10.1126/science.aaf1490

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

Nicholas McGranahan, Andrew J S Furness, Rachel Rosenthal, Sofie Ramskov Andersen, Rikke Birgitte Lyngaa, Sunil Kumar Saini, Mariam Jamal-Hanjani, Gareth A Wilson, Nicolai J. Birkbak, Crispin T Hiley, Thomas B K Watkins, Seema Shafi, Nirupa Murugaesu, Richard Mitter, Ayse U Akarca, Joseph Linares, Teresa Marafioti, Jake Y Henry, Eliezer M Van Allen, Diana MiaoBastian Schilling, Dirk Schadendorf, Levi A Garraway, Vladimir Makarov, Naiyer A Rizvi, Alexandra Snyder, Matthew D Hellmann, Taha Merghoub, Jedd D Wolchok, Sachet A Shukla, Catherine J Wu, Karl S Peggs, Timothy A Chan, Sine Reker Hadrup, Sergio A Quezada, Charles Swanton

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Abstract

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.

Original language	English
Journal	Science
Volume	351
Issue number	6280
Pages (from-to)	1463-1469
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.aaf1490
Publication status	Published - 2016

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McGranahan, N., Furness, A. J. S., Rosenthal, R., Andersen, S. R., Lyngaa, R. B., Saini, S. K., Jamal-Hanjani, M., Wilson, G. A., Birkbak, N. J., Hiley, C. T., Watkins, T. B. K., Shafi, S., Murugaesu, N., Mitter, R., Akarca, A. U., Linares, J., Marafioti, T., Henry, J. Y., Van Allen, E. M., ... Swanton, C. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science, 351(6280), 1463-1469. https://doi.org/10.1126/science.aaf1490

@article{c36e3271a3d946b6b0d1d3537ae20249,

title = "Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade",

abstract = "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. ",

author = "Nicholas McGranahan and Furness, {Andrew J S} and Rachel Rosenthal and Andersen, {Sofie Ramskov} and Lyngaa, {Rikke Birgitte} and Saini, {Sunil Kumar} and Mariam Jamal-Hanjani and Wilson, {Gareth A} and Birkbak, {Nicolai J.} and Hiley, {Crispin T} and Watkins, {Thomas B K} and Seema Shafi and Nirupa Murugaesu and Richard Mitter and Akarca, {Ayse U} and Joseph Linares and Teresa Marafioti and Henry, {Jake Y} and {Van Allen}, {Eliezer M} and Diana Miao and Bastian Schilling and Dirk Schadendorf and Garraway, {Levi A} and Vladimir Makarov and Rizvi, {Naiyer A} and Alexandra Snyder and Hellmann, {Matthew D} and Taha Merghoub and Wolchok, {Jedd D} and Shukla, {Sachet A} and Wu, {Catherine J} and Peggs, {Karl S} and Chan, {Timothy A} and Hadrup, {Sine Reker} and Quezada, {Sergio A} and Charles Swanton",

year = "2016",

doi = "10.1126/science.aaf1490",

language = "English",

volume = "351",

pages = "1463--1469",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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McGranahan, N, Furness, AJS, Rosenthal, R, Andersen, SR, Lyngaa, RB, Saini, SK, Jamal-Hanjani, M, Wilson, GA, Birkbak, NJ, Hiley, CT, Watkins, TBK, Shafi, S, Murugaesu, N, Mitter, R, Akarca, AU, Linares, J, Marafioti, T, Henry, JY, Van Allen, EM, Miao, D, Schilling, B, Schadendorf, D, Garraway, LA, Makarov, V, Rizvi, NA, Snyder, A, Hellmann, MD, Merghoub, T, Wolchok, JD, Shukla, SA, Wu, CJ, Peggs, KS, Chan, TA, Hadrup, SR, Quezada, SA & Swanton, C 2016, 'Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade', Science, vol. 351, no. 6280, pp. 1463-1469. https://doi.org/10.1126/science.aaf1490

TY - JOUR

T1 - Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

AU - McGranahan, Nicholas

AU - Furness, Andrew J S

AU - Rosenthal, Rachel

AU - Andersen, Sofie Ramskov

AU - Lyngaa, Rikke Birgitte

AU - Saini, Sunil Kumar

AU - Jamal-Hanjani, Mariam

AU - Wilson, Gareth A

AU - Birkbak, Nicolai J.

AU - Hiley, Crispin T

AU - Watkins, Thomas B K

AU - Shafi, Seema

AU - Murugaesu, Nirupa

AU - Mitter, Richard

AU - Akarca, Ayse U

AU - Linares, Joseph

AU - Marafioti, Teresa

AU - Henry, Jake Y

AU - Van Allen, Eliezer M

AU - Miao, Diana

AU - Schilling, Bastian

AU - Schadendorf, Dirk

AU - Garraway, Levi A

AU - Makarov, Vladimir

AU - Rizvi, Naiyer A

AU - Snyder, Alexandra

AU - Hellmann, Matthew D

AU - Merghoub, Taha

AU - Wolchok, Jedd D

AU - Shukla, Sachet A

AU - Wu, Catherine J

AU - Peggs, Karl S

AU - Chan, Timothy A

AU - Hadrup, Sine Reker

AU - Quezada, Sergio A

AU - Swanton, Charles

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1126/science.aaf1490

DO - 10.1126/science.aaf1490

M3 - Journal article

C2 - 26940869

SN - 0036-8075

VL - 351

SP - 1463

EP - 1469

JO - Science

JF - Science

IS - 6280

ER -

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

Abstract

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