Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Danish Memon; Adam J. Schoenfeld; Darwin Ye; George Fromm; Hira Rizvi; Xiang Zhang; Mohamed Reda Keddar; Divij Mathew; Kyung Jin Yoo; Jingya Qiu; Jayon Lihm; Jayalaksmi Miriyala; Jennifer L. Sauter; Jia Luo; Andrew Chow; Umesh K. Bhanot; Caroline McCarthy; Chad M. Vanderbilt; Cailian Liu; Mohsen Abu-Akeel; Andrew J. Plodkowski; Nicholas McGranahan; Marta Łuksza; Benjamin D. Greenbaum; Taha Merghoub; Ikbel Achour; J. Carl Barrett; Ross Stewart; Pedro Beltrao; Taylor H. Schreiber; Andy J. Minn; Martin L. Miller; Matthew D. Hellmann

doi:10.1016/j.ccell.2023.12.013

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Danish Memon, Adam J. Schoenfeld, Darwin Ye, George Fromm, Hira Rizvi, Xiang Zhang, Mohamed Reda Keddar, Divij Mathew, Kyung Jin Yoo, Jingya Qiu, Jayon Lihm, Jayalaksmi Miriyala, Jennifer L. Sauter, Jia Luo, Andrew Chow, Umesh K. Bhanot, Caroline McCarthy, Chad M. Vanderbilt, Cailian Liu, Mohsen Abu-AkeelAndrew J. Plodkowski, Nicholas McGranahan, Marta Łuksza, Benjamin D. Greenbaum, Taha Merghoub, Ikbel Achour, J. Carl Barrett, Ross Stewart, Pedro Beltrao, Taylor H. Schreiber, Andy J. Minn, Martin L. Miller, Matthew D. Hellmann

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5 Scopus citations

Abstract

Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.

Original language	English
Pages (from-to)	209-224.e9
Journal	Cancer Cell
Volume	42
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2023.12.013
State	Published - 12 Feb 2024

Keywords

Clonal selection
Genomics and Transcriptomics
Immune escape
Immune-checkpoint blockade
Interferon alpha/gamma response
Neoantigens
T cell exhaustion
Tumor heterogeneity
Type I and Type II Interferons
anti-PD-1 therapy

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10.1016/j.ccell.2023.12.013

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Memon, D., Schoenfeld, A. J., Ye, D., Fromm, G., Rizvi, H., Zhang, X., Keddar, M. R., Mathew, D., Yoo, K. J., Qiu, J., Lihm, J., Miriyala, J., Sauter, J. L., Luo, J., Chow, A., Bhanot, U. K., McCarthy, C., Vanderbilt, C. M., Liu, C., ... Hellmann, M. D. (2024). Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer. Cancer Cell, 42(2), 209-224.e9. https://doi.org/10.1016/j.ccell.2023.12.013

@article{7a48b38aa03f4130b2df89e0e58e0a8c,

title = "Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer",

abstract = "Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.",

keywords = "Clonal selection, Genomics and Transcriptomics, Immune escape, Immune-checkpoint blockade, Interferon alpha/gamma response, Neoantigens, T cell exhaustion, Tumor heterogeneity, Type I and Type II Interferons, anti-PD-1 therapy",

author = "Danish Memon and Schoenfeld, {Adam J.} and Darwin Ye and George Fromm and Hira Rizvi and Xiang Zhang and Keddar, {Mohamed Reda} and Divij Mathew and Yoo, {Kyung Jin} and Jingya Qiu and Jayon Lihm and Jayalaksmi Miriyala and Sauter, {Jennifer L.} and Jia Luo and Andrew Chow and Bhanot, {Umesh K.} and Caroline McCarthy and Vanderbilt, {Chad M.} and Cailian Liu and Mohsen Abu-Akeel and Plodkowski, {Andrew J.} and Nicholas McGranahan and Marta {\L}uksza and Greenbaum, {Benjamin D.} and Taha Merghoub and Ikbel Achour and Barrett, {J. Carl} and Ross Stewart and Pedro Beltrao and Schreiber, {Taylor H.} and Minn, {Andy J.} and Miller, {Martin L.} and Hellmann, {Matthew D.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = feb,

day = "12",

doi = "10.1016/j.ccell.2023.12.013",

language = "English",

volume = "42",

pages = "209--224.e9",

journal = "Cancer Cell",

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Memon, D, Schoenfeld, AJ, Ye, D, Fromm, G, Rizvi, H, Zhang, X, Keddar, MR, Mathew, D, Yoo, KJ, Qiu, J, Lihm, J, Miriyala, J, Sauter, JL, Luo, J, Chow, A, Bhanot, UK, McCarthy, C, Vanderbilt, CM, Liu, C, Abu-Akeel, M, Plodkowski, AJ, McGranahan, N, Łuksza, M, Greenbaum, BD, Merghoub, T, Achour, I, Barrett, JC, Stewart, R, Beltrao, P, Schreiber, TH, Minn, AJ, Miller, ML & Hellmann, MD 2024, 'Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer', Cancer Cell, vol. 42, no. 2, pp. 209-224.e9. https://doi.org/10.1016/j.ccell.2023.12.013

TY - JOUR

T1 - Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

AU - Memon, Danish

AU - Schoenfeld, Adam J.

AU - Ye, Darwin

AU - Fromm, George

AU - Rizvi, Hira

AU - Zhang, Xiang

AU - Keddar, Mohamed Reda

AU - Mathew, Divij

AU - Yoo, Kyung Jin

AU - Qiu, Jingya

AU - Lihm, Jayon

AU - Miriyala, Jayalaksmi

AU - Sauter, Jennifer L.

AU - Luo, Jia

AU - Chow, Andrew

AU - Bhanot, Umesh K.

AU - McCarthy, Caroline

AU - Vanderbilt, Chad M.

AU - Liu, Cailian

AU - Abu-Akeel, Mohsen

AU - Plodkowski, Andrew J.

AU - McGranahan, Nicholas

AU - Łuksza, Marta

AU - Greenbaum, Benjamin D.

AU - Merghoub, Taha

AU - Achour, Ikbel

AU - Barrett, J. Carl

AU - Stewart, Ross

AU - Beltrao, Pedro

AU - Schreiber, Taylor H.

AU - Minn, Andy J.

AU - Miller, Martin L.

AU - Hellmann, Matthew D.

PY - 2024/2/12

Y1 - 2024/2/12

N2 - Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.

AB - Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.

KW - Clonal selection

KW - Genomics and Transcriptomics

KW - Immune escape

KW - Immune-checkpoint blockade

KW - Interferon alpha/gamma response

KW - Neoantigens

KW - T cell exhaustion

KW - Tumor heterogeneity

KW - Type I and Type II Interferons

KW - anti-PD-1 therapy

UR - http://www.scopus.com/inward/record.url?scp=85183996238&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2023.12.013

DO - 10.1016/j.ccell.2023.12.013

M3 - Article

C2 - 38215748

AN - SCOPUS:85183996238

SN - 1535-6108

VL - 42

SP - 209-224.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Abstract

Keywords

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