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PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer

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PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer. / Stein, Alexander; Simnica, Donjete; Schultheiß, Christoph; Scholz, Rebekka; Tintelnot, Joseph; Gökkurt, Eray; von Wenserski, Lisa; Willscher, Edith; Paschold, Lisa; Sauer, Markus; Lorenzen, Sylvie; Riera-Knorrenschild, Jorge; Depenbusch, Reinhard; Ettrich, Thomas J; Dörfel, Steffen; Al-Batran, Salah-Eddin; Karthaus, Meinolf; Pelzer, Uwe; Waberer, Lisa; Hinke, Axel; Bauer, Marcus; Massa, Chiara; Seliger, Barbara; Wickenhauser, Claudia; Bokemeyer, Carsten; Hegewisch-Becker, Susanna; Binder, Mascha.

In: J IMMUNOTHER CANCER, Vol. 9, No. 7, e002844, 07.2021.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Stein, A, Simnica, D, Schultheiß, C, Scholz, R, Tintelnot, J, Gökkurt, E, von Wenserski, L, Willscher, E, Paschold, L, Sauer, M, Lorenzen, S, Riera-Knorrenschild, J, Depenbusch, R, Ettrich, TJ, Dörfel, S, Al-Batran, S-E, Karthaus, M, Pelzer, U, Waberer, L, Hinke, A, Bauer, M, Massa, C, Seliger, B, Wickenhauser, C, Bokemeyer, C, Hegewisch-Becker, S & Binder, M 2021, 'PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer', J IMMUNOTHER CANCER, vol. 9, no. 7, e002844. https://doi.org/10.1136/jitc-2021-002844

APA

Stein, A., Simnica, D., Schultheiß, C., Scholz, R., Tintelnot, J., Gökkurt, E., von Wenserski, L., Willscher, E., Paschold, L., Sauer, M., Lorenzen, S., Riera-Knorrenschild, J., Depenbusch, R., Ettrich, T. J., Dörfel, S., Al-Batran, S-E., Karthaus, M., Pelzer, U., Waberer, L., ... Binder, M. (2021). PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer. J IMMUNOTHER CANCER, 9(7), [e002844]. https://doi.org/10.1136/jitc-2021-002844

Vancouver

Stein A, Simnica D, Schultheiß C, Scholz R, Tintelnot J, Gökkurt E et al. PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer. J IMMUNOTHER CANCER. 2021 Jul;9(7). e002844. https://doi.org/10.1136/jitc-2021-002844

Bibtex

@article{42d61aa1a71b488cbcb72199ddc8ec13,
title = "PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer",
abstract = "BACKGROUND: In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.METHODS: We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.RESULTS: Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.CONCLUSION: The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.TRIAL REGISTRATION NUMBER: NCT03174405.",
author = "Alexander Stein and Donjete Simnica and Christoph Schulthei{\ss} and Rebekka Scholz and Joseph Tintelnot and Eray G{\"o}kkurt and {von Wenserski}, Lisa and Edith Willscher and Lisa Paschold and Markus Sauer and Sylvie Lorenzen and Jorge Riera-Knorrenschild and Reinhard Depenbusch and Ettrich, {Thomas J} and Steffen D{\"o}rfel and Salah-Eddin Al-Batran and Meinolf Karthaus and Uwe Pelzer and Lisa Waberer and Axel Hinke and Marcus Bauer and Chiara Massa and Barbara Seliger and Claudia Wickenhauser and Carsten Bokemeyer and Susanna Hegewisch-Becker and Mascha Binder",
note = "{\textcopyright} Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2021",
month = jul,
doi = "10.1136/jitc-2021-002844",
language = "English",
volume = "9",
journal = "J IMMUNOTHER CANCER",
issn = "2051-1426",
publisher = "BioMed Central Ltd.",
number = "7",

}

RIS

TY - JOUR

T1 - PD-L1 targeting and subclonal immune escape mediated by PD-L1 mutations in metastatic colorectal cancer

AU - Stein, Alexander

AU - Simnica, Donjete

AU - Schultheiß, Christoph

AU - Scholz, Rebekka

AU - Tintelnot, Joseph

AU - Gökkurt, Eray

AU - von Wenserski, Lisa

AU - Willscher, Edith

AU - Paschold, Lisa

AU - Sauer, Markus

AU - Lorenzen, Sylvie

AU - Riera-Knorrenschild, Jorge

AU - Depenbusch, Reinhard

AU - Ettrich, Thomas J

AU - Dörfel, Steffen

AU - Al-Batran, Salah-Eddin

AU - Karthaus, Meinolf

AU - Pelzer, Uwe

AU - Waberer, Lisa

AU - Hinke, Axel

AU - Bauer, Marcus

AU - Massa, Chiara

AU - Seliger, Barbara

AU - Wickenhauser, Claudia

AU - Bokemeyer, Carsten

AU - Hegewisch-Becker, Susanna

AU - Binder, Mascha

N1 - © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2021/7

Y1 - 2021/7

N2 - BACKGROUND: In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.METHODS: We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.RESULTS: Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.CONCLUSION: The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.TRIAL REGISTRATION NUMBER: NCT03174405.

AB - BACKGROUND: In patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC), immune checkpoint blockade is ineffective, and combinatorial approaches enhancing immunogenicity need exploration.METHODS: We treated 43 patients with predominantly microsatellite stable RAS/BRAF wild-type mCRC on a phase II trial combining chemotherapy with the epidermal growth factor receptor antibody cetuximab and the programmed cell death ligand 1 (PD-L1) antibody avelumab. We performed next-generation gene panel sequencing for mutational typing of tumors and liquid biopsy monitoring as well as digital droplet PCR to confirm individual mutations. Translational analyses included tissue immunohistochemistry, multispectral imaging and repertoire sequencing of tumor-infiltrating T cells. Detected PD-L1 mutations were mechanistically validated in CRISPR/Cas9-generated cell models using qRT-PCR, immunoblotting, flow cytometry, complement-dependent cytotoxicity assay, antibody-dependent cytotoxicity by natural killer cell degranulation assay and LDH release assay as well as live cell imaging of T cell mediated tumor cell killing.RESULTS: Circulating tumor DNA showed rapid clearance in the majority of patients mirroring a high rate of early tumor shrinkage. In 3 of 13 patients expressing the high-affinity Fcγ receptor 3a (FcγR3a), tumor subclones with PD-L1 mutations were selected that led to loss of tumor PD-L1 by nonsense-mediated RNA decay in PD-L1 K162fs and protein degradation in PD-L1 L88S. As a consequence, avelumab binding and antibody-dependent cytotoxicity were impaired, while T cell killing of these variant clones was increased. Interestingly, PD-L1 mutant subclones showed slow selection dynamics reversing on avelumab withdrawal and patients with such subclones had above-average treatment benefit. This suggested that the PD-L1 mutations mediated resistance to direct antitumor effects of avelumab, while at the same time loss of PD-L1 reduced biological fitness by enhanced T cell killing limiting subclonal expansion.CONCLUSION: The addition of avelumab to standard treatment appeared feasible and safe. PD-L1 mutations mediate subclonal immune escape to avelumab in some patients with mCRC expressing high-affinity FcγR3a, which may be a subset experiencing most selective pressure. Future trials evaluating the addition of avelumab to standard treatment in MSS mCRC are warranted especially in this patient subpopulation.TRIAL REGISTRATION NUMBER: NCT03174405.

U2 - 10.1136/jitc-2021-002844

DO - 10.1136/jitc-2021-002844

M3 - SCORING: Journal article

C2 - 34315821

VL - 9

JO - J IMMUNOTHER CANCER

JF - J IMMUNOTHER CANCER

SN - 2051-1426

IS - 7

M1 - e002844

ER -