Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8þ T cells

Maud Rijnders; Hayri E. Balcioglu; Debbie G.J. Robbrecht; Astrid A.M. Oostvogels; Rebecca Wijers; Maureen J.B. Aarts; Paul Hamberg; Geert J.L.H. van Leenders; J. Alberto Nakauma-González; Jens Voortman; Hans M. Westgeest; Joost L. Boormans; Ronald de Wit; Martijn P. Lolkema; Astrid A.M. van der Veldt; Reno Debets

doi:10.1158/1078-0432.CCR-20-3319

Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8^þ T cells

Maud Rijnders, Hayri E. Balcioglu, Debbie G.J. Robbrecht, Astrid A.M. Oostvogels, Rebecca Wijers, Maureen J.B. Aarts, Paul Hamberg, Geert J.L.H. van Leenders, J. Alberto Nakauma-González, Jens Voortman, Hans M. Westgeest, Joost L. Boormans, Ronald de Wit, Martijn P. Lolkema, Astrid A.M. van der Veldt, Reno Debets^*

^*Corresponding author for this work

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

2 Citations (Scopus)

Abstract

Purpose: PD-1 inhibition results in durable antitumor responses in a proportion of patients with metastatic urothelial cancer (mUC). The majority of patients, however, do not experience clinical benefit. In this study, we aimed to identify early changes in T-cell subsets that underlie anti–PD-1 efficacy in patients with mUC. Experimental Design: Paired samples were collected from peripheral blood, plasma, and metastatic lesions of 56 patients with mUC at baseline and weeks 6 and 12 after initiating pembrolizumab treatment (200 mg intravenously, every 3 weeks). Samples were analyzed using multiplex flow cytometry, ELISA, and in situ stainings, including cellular network analysis. Treatment response was evaluated as best overall response according to RECIST v1.1, and patients were classified as responder (complete or partial response) or nonresponder (progressive disease). Results: In responders, baseline fractions of CD4^þ T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1^þ CD4^þ T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BB^þ CD28^þ CD4^þ T cells increased at week 12. In metastatic lesions of responders, the baseline density of T helper-type 1 (Th1) cells, defined as T-bet^þ CD4^þ T cells, was higher as compared to nonresponders. Upon treatment, Th1 cells became localized in close proximity to CD8^þ T cells, CD11b^þ myeloid cells, and tumor cells. Conclusions: A decrease in the fraction of circulating PD-1^þ CD4^þ T cells, and juxtaposition of Th1, CD8^þ, and myeloid cells was associated with response to anti–PD-1 treatment in patients with mUC.

Original language	English
Pages (from-to)	215-226
Number of pages	12
Journal	Clinical Cancer Research
Volume	28
Issue number	1
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-3319
Publication status	Published - 1 Jan 2022

Bibliographical note

Funding Information:
M.J.B. Aarts reports grants from Pfizer outside the submitted work. J. Voortman reports personal fees from F. Hoffmann-La Roche, MSD Oncology, Merck, Astellas Pharma, TEVA, Sanofi, Ipsen, and Pfizer outside the submitted work. H.M. Westgeest reports personal fees and other support from Astellas; other support from Ipsen; and personal fees from Roche outside the submitted work. J.L. Boormans reports personal fees from BMS, MSD, Ambu, Eight Medical, and Janssen outside the submitted work. R. de Wit reports grants from Merck during the conduct of the study. R. de Wit also reports personal fees from Merck; grants and personal fees from Sanofi and Bayer; and personal fees from Astellas, Janssen, and Orion outside the submitted work. M.P. Lolkema reports grants and personal fees from MSD during the conduct of the study; M.P. Lolkema also reports grants and personal fees from JNJ, Sanofi, and Astellas, as well as personal fees from Amgen, Roche, Novartis, Incyte, Pfizer, Julius Clinical, and Servier outside the submitted work. A.A.M van der Veldt reports other support from BMS, MSD, Merck, Roche, Novartis, Eisai, Ipsen, Pierre Fabre, Pfizer, Sanofi, and Bayer outside the submitted work. R. Debets reports grants from MSD during the conduct of the study; R. Debets also reports other support from Pan Cancer T outside the submitted work, as well as a patent for European patent application no. 21184727.2 pending to Erasmus MC. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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10.1158/1078-0432.CCR-20-3319

Cite this

Rijnders, M., Balcioglu, H. E., Robbrecht, D. G. J., Oostvogels, A. A. M., Wijers, R., Aarts, M. J. B., Hamberg, P., van Leenders, G. J. L. H., Nakauma-González, J. A., Voortman, J., Westgeest, H. M., Boormans, J. L., de Wit, R., Lolkema, M. P., van der Veldt, A. A. M., & Debets, R. (2022). Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8^þ T cells. Clinical Cancer Research, 28(1), 215-226. https://doi.org/10.1158/1078-0432.CCR-20-3319

@article{8ed9843516304156b70077c8364d3c4b,

title = "Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8{\th} T cells",

abstract = "Purpose: PD-1 inhibition results in durable antitumor responses in a proportion of patients with metastatic urothelial cancer (mUC). The majority of patients, however, do not experience clinical benefit. In this study, we aimed to identify early changes in T-cell subsets that underlie anti–PD-1 efficacy in patients with mUC. Experimental Design: Paired samples were collected from peripheral blood, plasma, and metastatic lesions of 56 patients with mUC at baseline and weeks 6 and 12 after initiating pembrolizumab treatment (200 mg intravenously, every 3 weeks). Samples were analyzed using multiplex flow cytometry, ELISA, and in situ stainings, including cellular network analysis. Treatment response was evaluated as best overall response according to RECIST v1.1, and patients were classified as responder (complete or partial response) or nonresponder (progressive disease). Results: In responders, baseline fractions of CD4{\th} T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1{\th} CD4{\th} T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BB{\th} CD28{\th} CD4{\th} T cells increased at week 12. In metastatic lesions of responders, the baseline density of T helper-type 1 (Th1) cells, defined as T-bet{\th} CD4{\th} T cells, was higher as compared to nonresponders. Upon treatment, Th1 cells became localized in close proximity to CD8{\th} T cells, CD11b{\th} myeloid cells, and tumor cells. Conclusions: A decrease in the fraction of circulating PD-1{\th} CD4{\th} T cells, and juxtaposition of Th1, CD8{\th}, and myeloid cells was associated with response to anti–PD-1 treatment in patients with mUC.",

author = "Maud Rijnders and Balcioglu, {Hayri E.} and Robbrecht, {Debbie G.J.} and Oostvogels, {Astrid A.M.} and Rebecca Wijers and Aarts, {Maureen J.B.} and Paul Hamberg and {van Leenders}, {Geert J.L.H.} and Nakauma-Gonz{\'a}lez, {J. Alberto} and Jens Voortman and Westgeest, {Hans M.} and Boormans, {Joost L.} and {de Wit}, Ronald and Lolkema, {Martijn P.} and {van der Veldt}, {Astrid A.M.} and Reno Debets",

note = "Funding Information: M.J.B. Aarts reports grants from Pfizer outside the submitted work. J. Voortman reports personal fees from F. Hoffmann-La Roche, MSD Oncology, Merck, Astellas Pharma, TEVA, Sanofi, Ipsen, and Pfizer outside the submitted work. H.M. Westgeest reports personal fees and other support from Astellas; other support from Ipsen; and personal fees from Roche outside the submitted work. J.L. Boormans reports personal fees from BMS, MSD, Ambu, Eight Medical, and Janssen outside the submitted work. R. de Wit reports grants from Merck during the conduct of the study. R. de Wit also reports personal fees from Merck; grants and personal fees from Sanofi and Bayer; and personal fees from Astellas, Janssen, and Orion outside the submitted work. M.P. Lolkema reports grants and personal fees from MSD during the conduct of the study; M.P. Lolkema also reports grants and personal fees from JNJ, Sanofi, and Astellas, as well as personal fees from Amgen, Roche, Novartis, Incyte, Pfizer, Julius Clinical, and Servier outside the submitted work. A.A.M van der Veldt reports other support from BMS, MSD, Merck, Roche, Novartis, Eisai, Ipsen, Pierre Fabre, Pfizer, Sanofi, and Bayer outside the submitted work. R. Debets reports grants from MSD during the conduct of the study; R. Debets also reports other support from Pan Cancer T outside the submitted work, as well as a patent for European patent application no. 21184727.2 pending to Erasmus MC. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2022",

month = jan,

day = "1",

doi = "10.1158/1078-0432.CCR-20-3319",

language = "English",

volume = "28",

pages = "215--226",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "1",

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Rijnders, M , Balcioglu, HE , Robbrecht, DGJ , Oostvogels, AAM , Wijers, R, Aarts, MJB, Hamberg, P, van Leenders, GJLH , Nakauma-González, JA, Voortman, J, Westgeest, HM, Boormans, JL , de Wit, R , Lolkema, MP , van der Veldt, AAM & Debets, R 2022, 'Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8^þ T cells', Clinical Cancer Research, vol. 28, no. 1, pp. 215-226. https://doi.org/10.1158/1078-0432.CCR-20-3319

TY - JOUR

T1 - Anti–PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8þ T cells

AU - Rijnders, Maud

AU - Balcioglu, Hayri E.

AU - Robbrecht, Debbie G.J.

AU - Oostvogels, Astrid A.M.

AU - Wijers, Rebecca

AU - Aarts, Maureen J.B.

AU - Hamberg, Paul

AU - van Leenders, Geert J.L.H.

AU - Nakauma-González, J. Alberto

AU - Voortman, Jens

AU - Westgeest, Hans M.

AU - Boormans, Joost L.

AU - de Wit, Ronald

AU - Lolkema, Martijn P.

AU - van der Veldt, Astrid A.M.

AU - Debets, Reno

N1 - Funding Information: M.J.B. Aarts reports grants from Pfizer outside the submitted work. J. Voortman reports personal fees from F. Hoffmann-La Roche, MSD Oncology, Merck, Astellas Pharma, TEVA, Sanofi, Ipsen, and Pfizer outside the submitted work. H.M. Westgeest reports personal fees and other support from Astellas; other support from Ipsen; and personal fees from Roche outside the submitted work. J.L. Boormans reports personal fees from BMS, MSD, Ambu, Eight Medical, and Janssen outside the submitted work. R. de Wit reports grants from Merck during the conduct of the study. R. de Wit also reports personal fees from Merck; grants and personal fees from Sanofi and Bayer; and personal fees from Astellas, Janssen, and Orion outside the submitted work. M.P. Lolkema reports grants and personal fees from MSD during the conduct of the study; M.P. Lolkema also reports grants and personal fees from JNJ, Sanofi, and Astellas, as well as personal fees from Amgen, Roche, Novartis, Incyte, Pfizer, Julius Clinical, and Servier outside the submitted work. A.A.M van der Veldt reports other support from BMS, MSD, Merck, Roche, Novartis, Eisai, Ipsen, Pierre Fabre, Pfizer, Sanofi, and Bayer outside the submitted work. R. Debets reports grants from MSD during the conduct of the study; R. Debets also reports other support from Pan Cancer T outside the submitted work, as well as a patent for European patent application no. 21184727.2 pending to Erasmus MC. No disclosures were reported by the other authors. Publisher Copyright: © 2021 American Association for Cancer Research.

PY - 2022/1/1

Y1 - 2022/1/1

N2 - Purpose: PD-1 inhibition results in durable antitumor responses in a proportion of patients with metastatic urothelial cancer (mUC). The majority of patients, however, do not experience clinical benefit. In this study, we aimed to identify early changes in T-cell subsets that underlie anti–PD-1 efficacy in patients with mUC. Experimental Design: Paired samples were collected from peripheral blood, plasma, and metastatic lesions of 56 patients with mUC at baseline and weeks 6 and 12 after initiating pembrolizumab treatment (200 mg intravenously, every 3 weeks). Samples were analyzed using multiplex flow cytometry, ELISA, and in situ stainings, including cellular network analysis. Treatment response was evaluated as best overall response according to RECIST v1.1, and patients were classified as responder (complete or partial response) or nonresponder (progressive disease). Results: In responders, baseline fractions of CD4þ T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1þ CD4þ T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BBþ CD28þ CD4þ T cells increased at week 12. In metastatic lesions of responders, the baseline density of T helper-type 1 (Th1) cells, defined as T-betþ CD4þ T cells, was higher as compared to nonresponders. Upon treatment, Th1 cells became localized in close proximity to CD8þ T cells, CD11bþ myeloid cells, and tumor cells. Conclusions: A decrease in the fraction of circulating PD-1þ CD4þ T cells, and juxtaposition of Th1, CD8þ, and myeloid cells was associated with response to anti–PD-1 treatment in patients with mUC.

AB - Purpose: PD-1 inhibition results in durable antitumor responses in a proportion of patients with metastatic urothelial cancer (mUC). The majority of patients, however, do not experience clinical benefit. In this study, we aimed to identify early changes in T-cell subsets that underlie anti–PD-1 efficacy in patients with mUC. Experimental Design: Paired samples were collected from peripheral blood, plasma, and metastatic lesions of 56 patients with mUC at baseline and weeks 6 and 12 after initiating pembrolizumab treatment (200 mg intravenously, every 3 weeks). Samples were analyzed using multiplex flow cytometry, ELISA, and in situ stainings, including cellular network analysis. Treatment response was evaluated as best overall response according to RECIST v1.1, and patients were classified as responder (complete or partial response) or nonresponder (progressive disease). Results: In responders, baseline fractions of CD4þ T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1þ CD4þ T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BBþ CD28þ CD4þ T cells increased at week 12. In metastatic lesions of responders, the baseline density of T helper-type 1 (Th1) cells, defined as T-betþ CD4þ T cells, was higher as compared to nonresponders. Upon treatment, Th1 cells became localized in close proximity to CD8þ T cells, CD11bþ myeloid cells, and tumor cells. Conclusions: A decrease in the fraction of circulating PD-1þ CD4þ T cells, and juxtaposition of Th1, CD8þ, and myeloid cells was associated with response to anti–PD-1 treatment in patients with mUC.

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DO - 10.1158/1078-0432.CCR-20-3319

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