Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer

Scott Gettinger; Jungmin Choi; Katherine Hastings; Anna Truini; Ila Datar; Ryan Sowell; Anna Wurtz; Weilai Dong; Guoping Cai; Mary Ann Melnick; Victor Y. Du; Joseph Schlessinger; Sarah B. Goldberg; Anne Chiang; Miguel F. Sanmamed; Ignacio Melero; Jackeline Agorreta; Luis M. Montuenga; Richard Lifton; Soldano Ferrone; Paula Kavathas; David L. Rimm; Susan M. Kaech; Kurt Schalper; Roy S. Herbst; Katerina Politi

doi:10.1158/2159-8290.CD-17-0593

Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer

Scott Gettinger, Jungmin Choi, Katherine Hastings, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Victor Y. Du, Joseph Schlessinger, Sarah B. Goldberg, Anne Chiang, Miguel F. Sanmamed, Ignacio Melero, Jackeline Agorreta, Luis M. Montuenga, Richard Lifton, Soldano FerronePaula Kavathas, David L. Rimm, Susan M. Kaech, Kurt Schalper, Roy S. Herbst, Katerina Politi

Research output: Contribution to journal › Article › peer-review

414 Citations (Scopus)

Abstract

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer.

Original language	English
Pages (from-to)	1420-1435
Number of pages	16
Journal	Cancer Discovery
Volume	7
Issue number	12
DOIs	https://doi.org/10.1158/2159-8290.CD-17-0593
Publication status	Published - 2017 Dec
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the following NIH/NCI grants: the Yale SPORE in Lung Cancer (P50CA196530) to R.S. Herbst, R01CA195720 to K. Politi and S.M. Kaech, and F32CA210516 to K. Hastings. Additional support came from a Stand Up To Cancer Lung Dream grant, Department of Defense Lung Cancer Research Program Career Development Award #LC150383 to K. Schalper, a Lung Cancer Research Foundation grant to K. Schalper, a fellowship from the Italian Association for Cancer Research (AIRC) to A. Truini, the Leslie H. Warner Fellowship to K. Hastings, The Diane and David Heller Foundation, The Beatrice Klienberg Neuwirth Research Program, and the Melissa Marottoli Hogan Foundation. Yale Cancer Center Shared Resources used in this article were in part supported by NIH/NCI Cancer Center Support Grant P30 CA016359.

Funding Information:
S. Gettinger is a consultant/advisory board member for BMS, ARIAD, and Pfizer. S.B. Goldberg is a consultant/advisory board member for AstraZeneca. I. Melero reports receiving commercial research grants from Alligator, BMS, and Roche and is a consultant/advisory board member for BMS, Roche, Alligator, Bayer, Lilly, Novartis, and AstraZeneca. D.L. Rimm is a consultant/advisory board member for Perkin Elmer, BMS, AstraZeneca, Cell Signaling Technology, and Merck. K.A. Schalper reports receiving commercial research grants from Tesaro Inc., Onkaido Therapeutics, Takeda, and Surface Oncology, has received honoraria from the speakers bureaus of Takeda and Merck, and is a consultant/advisory board member for Celgene. K. Politi reports receiving commercial research grants from AstraZeneca and Roche and is a consultant/advisory board member for AstraZeneca, Novartis, and Merck. No potential conflicts of interest were disclosed by the other authors.

Publisher Copyright:
© 2017 American Association for Cancer Research.

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-17-0593

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Gettinger, S., Choi, J., Hastings, K., Truini, A., Datar, I., Sowell, R., Wurtz, A., Dong, W., Cai, G., Melnick, M. A., Du, V. Y., Schlessinger, J., Goldberg, S. B., Chiang, A., Sanmamed, M. F., Melero, I., Agorreta, J., Montuenga, L. M., Lifton, R., ... Politi, K. (2017). Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discovery, 7(12), 1420-1435. https://doi.org/10.1158/2159-8290.CD-17-0593

Gettinger, S, Choi, J, Hastings, K, Truini, A, Datar, I, Sowell, R, Wurtz, A, Dong, W, Cai, G, Melnick, MA, Du, VY, Schlessinger, J, Goldberg, SB, Chiang, A, Sanmamed, MF, Melero, I, Agorreta, J, Montuenga, LM, Lifton, R, Ferrone, S, Kavathas, P, Rimm, DL, Kaech, SM, Schalper, K, Herbst, RS & Politi, K 2017, 'Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer', Cancer Discovery, vol. 7, no. 12, pp. 1420-1435. https://doi.org/10.1158/2159-8290.CD-17-0593

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abstract = "Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer.",

author = "Scott Gettinger and Jungmin Choi and Katherine Hastings and Anna Truini and Ila Datar and Ryan Sowell and Anna Wurtz and Weilai Dong and Guoping Cai and Melnick, {Mary Ann} and Du, {Victor Y.} and Joseph Schlessinger and Goldberg, {Sarah B.} and Anne Chiang and Sanmamed, {Miguel F.} and Ignacio Melero and Jackeline Agorreta and Montuenga, {Luis M.} and Richard Lifton and Soldano Ferrone and Paula Kavathas and Rimm, {David L.} and Kaech, {Susan M.} and Kurt Schalper and Herbst, {Roy S.} and Katerina Politi",

note = "Funding Information: This work was supported by the following NIH/NCI grants: the Yale SPORE in Lung Cancer (P50CA196530) to R.S. Herbst, R01CA195720 to K. Politi and S.M. Kaech, and F32CA210516 to K. Hastings. Additional support came from a Stand Up To Cancer Lung Dream grant, Department of Defense Lung Cancer Research Program Career Development Award #LC150383 to K. Schalper, a Lung Cancer Research Foundation grant to K. Schalper, a fellowship from the Italian Association for Cancer Research (AIRC) to A. Truini, the Leslie H. Warner Fellowship to K. Hastings, The Diane and David Heller Foundation, The Beatrice Klienberg Neuwirth Research Program, and the Melissa Marottoli Hogan Foundation. Yale Cancer Center Shared Resources used in this article were in part supported by NIH/NCI Cancer Center Support Grant P30 CA016359. Funding Information: S. Gettinger is a consultant/advisory board member for BMS, ARIAD, and Pfizer. S.B. Goldberg is a consultant/advisory board member for AstraZeneca. I. Melero reports receiving commercial research grants from Alligator, BMS, and Roche and is a consultant/advisory board member for BMS, Roche, Alligator, Bayer, Lilly, Novartis, and AstraZeneca. D.L. Rimm is a consultant/advisory board member for Perkin Elmer, BMS, AstraZeneca, Cell Signaling Technology, and Merck. K.A. Schalper reports receiving commercial research grants from Tesaro Inc., Onkaido Therapeutics, Takeda, and Surface Oncology, has received honoraria from the speakers bureaus of Takeda and Merck, and is a consultant/advisory board member for Celgene. K. Politi reports receiving commercial research grants from AstraZeneca and Roche and is a consultant/advisory board member for AstraZeneca, Novartis, and Merck. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

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doi = "10.1158/2159-8290.CD-17-0593",

language = "English",

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T1 - Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer

AU - Gettinger, Scott

AU - Choi, Jungmin

AU - Hastings, Katherine

AU - Truini, Anna

AU - Datar, Ila

AU - Sowell, Ryan

AU - Wurtz, Anna

AU - Dong, Weilai

AU - Cai, Guoping

AU - Melnick, Mary Ann

AU - Du, Victor Y.

AU - Schlessinger, Joseph

AU - Goldberg, Sarah B.

AU - Chiang, Anne

AU - Sanmamed, Miguel F.

AU - Melero, Ignacio

AU - Agorreta, Jackeline

AU - Montuenga, Luis M.

AU - Lifton, Richard

AU - Ferrone, Soldano

AU - Kavathas, Paula

AU - Rimm, David L.

AU - Kaech, Susan M.

AU - Schalper, Kurt

AU - Herbst, Roy S.

AU - Politi, Katerina

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PY - 2017/12

Y1 - 2017/12

N2 - Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer.

AB - Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer. SIGNIFICANCE: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer.

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Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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