Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

Sachet A. Shukla; Pavan Bachireddy; Bastian Schilling; Christina Galonska; Qian Zhan; Clyde Bango; Rupert Langer; Patrick C. Lee; Daniel Gusenleitner; Derin B. Keskin; Mehrtash Babadi; Arman Mohammad; Andreas Gnirke; Kendell Clement; Zachary J. Cartun; Eliezer M. Van Allen; Diana Miao; Ying Huang; Alexandra Snyder; Taha Merghoub; Jedd D. Wolchok; Levi A. Garraway; Alexander Meissner; Jeffrey S. Weber; Nir Hacohen; Donna Neuberg; Patrick R. Potts; George F. Murphy; Christine G. Lian; Dirk Schadendorf; F. Stephen Hodi; Catherine J. Wu

doi:10.1016/j.cell.2018.03.026

Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

Sachet A. Shukla, Pavan Bachireddy, Bastian Schilling, Christina Galonska, Qian Zhan, Clyde Bango, Rupert Langer, Patrick C. Lee, Daniel Gusenleitner, Derin B. Keskin, Mehrtash Babadi, Arman Mohammad, Andreas Gnirke, Kendell Clement, Zachary J. Cartun, Eliezer M. Van Allen, Diana Miao, Ying Huang, Alexandra Snyder, Taha MerghoubJedd D. Wolchok, Levi A. Garraway, Alexander Meissner, Jeffrey S. Weber, Nir Hacohen, Donna Neuberg, Patrick R. Potts, George F. Murphy, Christine G. Lian, Dirk Schadendorf, F. Stephen Hodi, Catherine J. Wu

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105 Scopus citations

Abstract

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors. Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.

Original language	English (US)
Pages (from-to)	624-633.e8
Journal	Cell
Volume	173
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.03.026
State	Published - Apr 19 2018
Externally published	Yes

Keywords

CTLA-4
MAGE-A
PD-1
autophagy
cancer-germline antigen
checkpoint blockade
immunogenomics
immunotherapy
ipilimumab
melanoma

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2018.03.026

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Shukla, S. A., Bachireddy, P., Schilling, B., Galonska, C., Zhan, Q., Bango, C., Langer, R., Lee, P. C., Gusenleitner, D., Keskin, D. B., Babadi, M., Mohammad, A., Gnirke, A., Clement, K., Cartun, Z. J., Van Allen, E. M., Miao, D., Huang, Y., Snyder, A., ... Wu, C. J. (2018). Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade. Cell, 173(3), 624-633.e8. https://doi.org/10.1016/j.cell.2018.03.026

Shukla, SA , Bachireddy, P, Schilling, B, Galonska, C, Zhan, Q, Bango, C, Langer, R, Lee, PC, Gusenleitner, D, Keskin, DB, Babadi, M, Mohammad, A, Gnirke, A, Clement, K, Cartun, ZJ, Van Allen, EM, Miao, D, Huang, Y, Snyder, A, Merghoub, T, Wolchok, JD, Garraway, LA, Meissner, A, Weber, JS, Hacohen, N, Neuberg, D, Potts, PR, Murphy, GF, Lian, CG, Schadendorf, D, Hodi, FS & Wu, CJ 2018, 'Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade', Cell, vol. 173, no. 3, pp. 624-633.e8. https://doi.org/10.1016/j.cell.2018.03.026

@article{7748dc8a1536405193c702070ca8d0f0,

title = "Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade",

abstract = "CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors. Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.",

keywords = "CTLA-4, MAGE-A, PD-1, autophagy, cancer-germline antigen, checkpoint blockade, immunogenomics, immunotherapy, ipilimumab, melanoma",

author = "Shukla, {Sachet A.} and Pavan Bachireddy and Bastian Schilling and Christina Galonska and Qian Zhan and Clyde Bango and Rupert Langer and Lee, {Patrick C.} and Daniel Gusenleitner and Keskin, {Derin B.} and Mehrtash Babadi and Arman Mohammad and Andreas Gnirke and Kendell Clement and Cartun, {Zachary J.} and {Van Allen}, {Eliezer M.} and Diana Miao and Ying Huang and Alexandra Snyder and Taha Merghoub and Wolchok, {Jedd D.} and Garraway, {Levi A.} and Alexander Meissner and Weber, {Jeffrey S.} and Nir Hacohen and Donna Neuberg and Potts, {Patrick R.} and Murphy, {George F.} and Lian, {Christine G.} and Dirk Schadendorf and Hodi, {F. Stephen} and Wu, {Catherine J.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = apr,

day = "19",

doi = "10.1016/j.cell.2018.03.026",

language = "English (US)",

volume = "173",

pages = "624--633.e8",

journal = "Cell",

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T1 - Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

AU - Shukla, Sachet A.

AU - Bachireddy, Pavan

AU - Schilling, Bastian

AU - Galonska, Christina

AU - Zhan, Qian

AU - Bango, Clyde

AU - Langer, Rupert

AU - Lee, Patrick C.

AU - Gusenleitner, Daniel

AU - Keskin, Derin B.

AU - Babadi, Mehrtash

AU - Mohammad, Arman

AU - Gnirke, Andreas

AU - Clement, Kendell

AU - Cartun, Zachary J.

AU - Van Allen, Eliezer M.

AU - Miao, Diana

AU - Huang, Ying

AU - Snyder, Alexandra

AU - Merghoub, Taha

AU - Wolchok, Jedd D.

AU - Garraway, Levi A.

AU - Meissner, Alexander

AU - Weber, Jeffrey S.

AU - Hacohen, Nir

AU - Neuberg, Donna

AU - Potts, Patrick R.

AU - Murphy, George F.

AU - Lian, Christine G.

AU - Schadendorf, Dirk

AU - Hodi, F. Stephen

AU - Wu, Catherine J.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors. Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.

AB - CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors. Increased expression of a subcluster of MAGE-A cancer-germline antigens predicts resistance specific to CTLA-4, but not PD-1, blockade, and its association with autophagy suppression implicates the role of autophagy in regulating primary resistance to anti-CTLA-4 therapy in melanoma patients.

KW - CTLA-4

KW - MAGE-A

KW - PD-1

KW - autophagy

KW - cancer-germline antigen

KW - checkpoint blockade

KW - immunogenomics

KW - immunotherapy

KW - ipilimumab

KW - melanoma

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UR - http://www.scopus.com/inward/citedby.url?scp=85044983675&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.03.026

DO - 10.1016/j.cell.2018.03.026

M3 - Article

C2 - 29656892

AN - SCOPUS:85044983675

SN - 0092-8674

VL - 173

SP - 624-633.e8

JO - Cell

JF - Cell

IS - 3

ER -

Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade

Abstract

Keywords

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