Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population

Anthony Z. Wang; Bryce L. Mashimo; Maximilian O. Schaettler; Ngima D. Sherpa; Lydia A. Leavitt; Alexandra J. Livingstone; Saad M. Khan; Mao Li; Markus I. Anzaldua-Campos; Joseph D. Bradley; Eric C. Leuthardt; Albert H. Kim; Joshua L. Dowling; Michael R. Chicoine; Pamela S. Jones; Bryan D. Choi; Daniel P. Cahill; Bob S. Carter; Allegra A. Petti; Tanner M. Johanns; Gavin P. Dunn

doi:10.1158/2159-8290.CD-23-0913

Glioblastoma-Infiltrating CD8⁺ T Cells Are Predominantly a Clonally Expanded GZMK⁺ Effector Population

Anthony Z. Wang, Bryce L. Mashimo, Maximilian O. Schaettler, Ngima D. Sherpa, Lydia A. Leavitt, Alexandra J. Livingstone, Saad M. Khan, Mao Li, Markus I. Anzaldua-Campos, Joseph D. Bradley, Eric C. Leuthardt, Albert H. Kim, Joshua L. Dowling, Michael R. Chicoine, Pamela S. Jones, Bryan D. Choi, Daniel P. Cahill, Bob S. Carter, Allegra A. Petti, Tanner M. JohannsGavin P. Dunn

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2 Scopus citations

Abstract

Recent clinical trials have highlighted the limited efficacy of T cell–based immuno-therapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8⁺ TIL landscape reveals an enrichment of clonally expanded GZMK⁺ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8⁺ T-cell population in GBM TIL. These data suggest that GZMK⁺ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.

Original language	English
Pages (from-to)	1106-1131
Number of pages	26
Journal	Cancer discovery
Volume	14
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-23-0913
State	Published - Jun 1 2024

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Wang, A. Z., Mashimo, B. L., Schaettler, M. O., Sherpa, N. D., Leavitt, L. A., Livingstone, A. J., Khan, S. M., Li, M., Anzaldua-Campos, M. I., Bradley, J. D., Leuthardt, E. C., Kim, A. H., Dowling, J. L., Chicoine, M. R., Jones, P. S., Choi, B. D., Cahill, D. P., Carter, B. S., Petti, A. A., ... Dunn, G. P. (2024). Glioblastoma-Infiltrating CD8⁺ T Cells Are Predominantly a Clonally Expanded GZMK⁺ Effector Population. Cancer discovery, 14(6), 1106-1131. https://doi.org/10.1158/2159-8290.CD-23-0913

@article{9e3192d1c00c4fe8bededc80c95299a3,

title = "Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population",

abstract = "Recent clinical trials have highlighted the limited efficacy of T cell–based immuno-therapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.",

author = "Wang, {Anthony Z.} and Mashimo, {Bryce L.} and Schaettler, {Maximilian O.} and Sherpa, {Ngima D.} and Leavitt, {Lydia A.} and Livingstone, {Alexandra J.} and Khan, {Saad M.} and Mao Li and Anzaldua-Campos, {Markus I.} and Bradley, {Joseph D.} and Leuthardt, {Eric C.} and Kim, {Albert H.} and Dowling, {Joshua L.} and Chicoine, {Michael R.} and Jones, {Pamela S.} and Choi, {Bryan D.} and Cahill, {Daniel P.} and Carter, {Bob S.} and Petti, {Allegra A.} and Johanns, {Tanner M.} and Dunn, {Gavin P.}",

note = "Publisher Copyright: {\textcopyright} 2024 American Association for Cancer Research.",

year = "2024",

month = jun,

day = "1",

doi = "10.1158/2159-8290.CD-23-0913",

language = "English",

volume = "14",

pages = "1106--1131",

journal = "Cancer discovery",

issn = "2159-8274",

number = "6",

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Wang, AZ, Mashimo, BL, Schaettler, MO, Sherpa, ND, Leavitt, LA, Livingstone, AJ, Khan, SM, Li, M, Anzaldua-Campos, MI, Bradley, JD, Leuthardt, EC , Kim, AH , Dowling, JL, Chicoine, MR, Jones, PS, Choi, BD, Cahill, DP, Carter, BS, Petti, AA, Johanns, TM & Dunn, GP 2024, 'Glioblastoma-Infiltrating CD8⁺ T Cells Are Predominantly a Clonally Expanded GZMK⁺ Effector Population', Cancer discovery, vol. 14, no. 6, pp. 1106-1131. https://doi.org/10.1158/2159-8290.CD-23-0913

TY - JOUR

T1 - Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population

AU - Wang, Anthony Z.

AU - Mashimo, Bryce L.

AU - Schaettler, Maximilian O.

AU - Sherpa, Ngima D.

AU - Leavitt, Lydia A.

AU - Livingstone, Alexandra J.

AU - Khan, Saad M.

AU - Li, Mao

AU - Anzaldua-Campos, Markus I.

AU - Bradley, Joseph D.

AU - Leuthardt, Eric C.

AU - Kim, Albert H.

AU - Dowling, Joshua L.

AU - Chicoine, Michael R.

AU - Jones, Pamela S.

AU - Choi, Bryan D.

AU - Cahill, Daniel P.

AU - Carter, Bob S.

AU - Petti, Allegra A.

AU - Johanns, Tanner M.

AU - Dunn, Gavin P.

PY - 2024/6/1

Y1 - 2024/6/1

N2 - Recent clinical trials have highlighted the limited efficacy of T cell–based immuno-therapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.

AB - Recent clinical trials have highlighted the limited efficacy of T cell–based immuno-therapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications.

UR - http://www.scopus.com/inward/record.url?scp=85195226830&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-23-0913

DO - 10.1158/2159-8290.CD-23-0913

M3 - Article

C2 - 38416133

AN - SCOPUS:85195226830

SN - 2159-8274

VL - 14

SP - 1106

EP - 1131

JO - Cancer discovery

JF - Cancer discovery

IS - 6

ER -

Glioblastoma-Infiltrating CD8⁺ T Cells Are Predominantly a Clonally Expanded GZMK⁺ Effector Population

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