Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

Jeppe Sejerø Holm; Samuel A. Funt; Annie Borch; Kamilla Kjærgaard Munk; Anne-Mette Bjerregaard; James L. Reading; Colleen Maher; Ashley Regazzi; Phillip Wong; Hikmat Al-Ahmadie; Gopa Iyer; Tripti Tamhane; Amalie Kai Bentzen; Nana Overgaard Herschend; Susan De Wolf; Alexandra Snyder; Taha Merghoub; Jedd D. Wolchok; Morten Nielsen; Jonathan E. Rosenberg; Dean F. Bajorin; Sine Reker Hadrup

doi:10.1038/s41467-022-29342-0

Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

Jeppe Sejerø Holm, Samuel A. Funt, Annie Borch, Kamilla Kjærgaard Munk, Anne-Mette Bjerregaard, James L. Reading, Colleen Maher, Ashley Regazzi, Phillip Wong, Hikmat Al-Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan De Wolf, Alexandra Snyder, Taha Merghoub, Jedd D. Wolchok, Morten Nielsen, Jonathan E. RosenbergDean F. Bajorin, Sine Reker Hadrup^*

^*Corresponding author for this work

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Abstract

CD8⁺ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8⁺ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8⁺ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1⁺ Ki67⁺ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8⁺ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.

Original language	English
Article number	1935
Journal	Nature Communications
Volume	13
Number of pages	17
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-022-29342-0
Publication status	Published - 2022

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Holm, J. S., Funt, S. A., Borch, A., Munk, K. K., Bjerregaard, A.-M., Reading, J. L., Maher, C., Regazzi, A., Wong, P., Al-Ahmadie, H., Iyer, G., Tamhane, T., Bentzen, A. K., Herschend, N. O., De Wolf, S., Snyder, A., Merghoub, T., Wolchok, J. D., Nielsen, M., ... Hadrup, S. R. (2022). Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma. Nature Communications, 13, Article 1935. https://doi.org/10.1038/s41467-022-29342-0

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title = "Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma",

abstract = "CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.",

author = "Holm, {Jeppe Sejer{\o}} and Funt, {Samuel A.} and Annie Borch and Munk, {Kamilla Kj{\ae}rgaard} and Anne-Mette Bjerregaard and Reading, {James L.} and Colleen Maher and Ashley Regazzi and Phillip Wong and Hikmat Al-Ahmadie and Gopa Iyer and Tripti Tamhane and Bentzen, {Amalie Kai} and Herschend, {Nana Overgaard} and {De Wolf}, Susan and Alexandra Snyder and Taha Merghoub and Wolchok, {Jedd D.} and Morten Nielsen and Rosenberg, {Jonathan E.} and Bajorin, {Dean F.} and Hadrup, {Sine Reker}",

year = "2022",

doi = "10.1038/s41467-022-29342-0",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Holm, JS, Funt, SA, Borch, A , Munk, KK, Bjerregaard, A-M, Reading, JL, Maher, C, Regazzi, A, Wong, P, Al-Ahmadie, H, Iyer, G, Tamhane, T, Bentzen, AK, Herschend, NO, De Wolf, S, Snyder, A, Merghoub, T, Wolchok, JD, Nielsen, M, Rosenberg, JE, Bajorin, DF & Hadrup, SR 2022, 'Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma', Nature Communications, vol. 13, 1935. https://doi.org/10.1038/s41467-022-29342-0

TY - JOUR

T1 - Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

AU - Holm, Jeppe Sejerø

AU - Funt, Samuel A.

AU - Borch, Annie

AU - Munk, Kamilla Kjærgaard

AU - Bjerregaard, Anne-Mette

AU - Reading, James L.

AU - Maher, Colleen

AU - Regazzi, Ashley

AU - Wong, Phillip

AU - Al-Ahmadie, Hikmat

AU - Iyer, Gopa

AU - Tamhane, Tripti

AU - Bentzen, Amalie Kai

AU - Herschend, Nana Overgaard

AU - De Wolf, Susan

AU - Snyder, Alexandra

AU - Merghoub, Taha

AU - Wolchok, Jedd D.

AU - Nielsen, Morten

AU - Rosenberg, Jonathan E.

AU - Bajorin, Dean F.

AU - Hadrup, Sine Reker

PY - 2022

Y1 - 2022

N2 - CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.

AB - CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.

U2 - 10.1038/s41467-022-29342-0

DO - 10.1038/s41467-022-29342-0

M3 - Journal article

C2 - 35410325

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 1935

ER -

Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma

Abstract

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