TY - JOUR
T1 - Anti-PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8(+) T cells
AU - Rijnders, M.
AU - Balcioglu, H.E.
AU - Robbrecht, D.G.J.
AU - Oostvogels, A.A.M.
AU - Wijers, R.
AU - Aarts, M.J.B.
AU - Hamberg, P.
AU - van Leenders, G.J.L.H.
AU - Nakauma-Gonzalez, J.A.
AU - Voortman, J.
AU - Westgeest, H.M.
AU - Boormans, J.L.
AU - de Wit, R.
AU - Lolkema, M.P.
AU - van der Veldt, A.A.M.
AU - Debets, R.
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 CD4(+) T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1(+) CD4(+) T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BB(+) CD28(+) CD4(+) 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(+) CD4(+) T cells, was higher as compared to non-responders. Upon treatment, Th1 cells became localized in close proximity to CD8(+) T cells, CD11b(+) myeloid cells, and tumor cells.Conclusions: A decrease in the fraction of circulating PD-1(+) CD4(+) T cells, and juxtaposition of Th1, CD8(+), 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 CD4(+) T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1(+) CD4(+) T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BB(+) CD28(+) CD4(+) 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(+) CD4(+) T cells, was higher as compared to non-responders. Upon treatment, Th1 cells became localized in close proximity to CD8(+) T cells, CD11b(+) myeloid cells, and tumor cells.Conclusions: A decrease in the fraction of circulating PD-1(+) CD4(+) T cells, and juxtaposition of Th1, CD8(+), and myeloid cells was associated with response to anti-PD-1 treatment in patients with mUC.
KW - CISPLATIN-INELIGIBLE PATIENTS
KW - SINGLE-ARM
KW - B-CELLS
KW - IMMUNOTHERAPY
KW - MULTICENTER
KW - THERAPY
KW - SURVIVAL
KW - CD4(+)
KW - PEMBROLIZUMAB
KW - ATEZOLIZUMAB
U2 - 10.1158/1078-0432.ccr-20-3319
DO - 10.1158/1078-0432.ccr-20-3319
M3 - Article
C2 - 34615720
SN - 1078-0432
VL - 28
SP - 215
EP - 226
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -