Immuno-transcriptomic profiling of extracranial pediatric solid malignancies

Andrew S. Brohl; Sivasish Sindiri; Jun S. Wei; David Milewski; Hsien Chao Chou; Young K. Song; Xinyu Wen; Jeetendra Kumar; Hue V. Reardon; Uma S. Mudunuri; Jack R. Collins; Sushma Nagaraj; Vineela Gangalapudi; Manoj Tyagi; Yuelin J. Zhu; Katherine E. Masih; Marielle E. Yohe; Jack F. Shern; Yue Qi; Udayan Guha; Daniel Catchpoole; Rimas J. Orentas; Igor B. Kuznetsov; Nicolas J. Llosa; John A. Ligon; Brian K. Turpin; Daniel G. Leino; Shintaro Iwata; Irene L. Andrulis; Jay S. Wunder; Silvia R.C. Toledo; Paul S. Meltzer; Ching Lau; Beverly A. Teicher; Heather Magnan; Marc Ladanyi; Javed Khan

doi:10.1016/j.celrep.2021.110047

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies

Andrew S. Brohl, Sivasish Sindiri, Jun S. Wei, David Milewski, Hsien Chao Chou, Young K. Song, Xinyu Wen, Jeetendra Kumar, Hue V. Reardon, Uma S. Mudunuri, Jack R. Collins, Sushma Nagaraj, Vineela Gangalapudi, Manoj Tyagi, Yuelin J. Zhu, Katherine E. Masih, Marielle E. Yohe, Jack F. Shern, Yue Qi, Udayan GuhaDaniel Catchpoole, Rimas J. Orentas, Igor B. Kuznetsov, Nicolas J. Llosa, John A. Ligon, Brian K. Turpin, Daniel G. Leino, Shintaro Iwata, Irene L. Andrulis, Jay S. Wunder, Silvia R.C. Toledo, Paul S. Meltzer, Ching Lau, Beverly A. Teicher, Heather Magnan, Marc Ladanyi, Javed Khan

School of Medicine

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

Abstract

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Original language	English (US)
Article number	110047
Journal	Cell Reports
Volume	37
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.110047
State	Published - Nov 23 2021

Keywords

PRAME
RNA sequencing
T cell receptor
adoptive cell therapy
immunogenomics
immunopeptidomics
pediatric oncology
tumor-infiltrating lymphocytes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.110047

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Brohl, A. S., Sindiri, S., Wei, J. S., Milewski, D., Chou, H. C., Song, Y. K., Wen, X., Kumar, J., Reardon, H. V., Mudunuri, U. S., Collins, J. R., Nagaraj, S., Gangalapudi, V., Tyagi, M., Zhu, Y. J., Masih, K. E., Yohe, M. E., Shern, J. F., Qi, Y., ... Khan, J. (2021). Immuno-transcriptomic profiling of extracranial pediatric solid malignancies. Cell Reports, 37(8), Article 110047. https://doi.org/10.1016/j.celrep.2021.110047

Brohl, AS, Sindiri, S, Wei, JS, Milewski, D, Chou, HC, Song, YK, Wen, X, Kumar, J, Reardon, HV, Mudunuri, US, Collins, JR, Nagaraj, S, Gangalapudi, V, Tyagi, M, Zhu, YJ, Masih, KE, Yohe, ME, Shern, JF, Qi, Y, Guha, U, Catchpoole, D, Orentas, RJ, Kuznetsov, IB, Llosa, NJ, Ligon, JA, Turpin, BK, Leino, DG, Iwata, S, Andrulis, IL, Wunder, JS, Toledo, SRC, Meltzer, PS, Lau, C, Teicher, BA, Magnan, H, Ladanyi, M & Khan, J 2021, 'Immuno-transcriptomic profiling of extracranial pediatric solid malignancies', Cell Reports, vol. 37, no. 8, 110047. https://doi.org/10.1016/j.celrep.2021.110047

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title = "Immuno-transcriptomic profiling of extracranial pediatric solid malignancies",

abstract = "We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.",

keywords = "PRAME, RNA sequencing, T cell receptor, adoptive cell therapy, immunogenomics, immunopeptidomics, pediatric oncology, tumor-infiltrating lymphocytes",

author = "Brohl, {Andrew S.} and Sivasish Sindiri and Wei, {Jun S.} and David Milewski and Chou, {Hsien Chao} and Song, {Young K.} and Xinyu Wen and Jeetendra Kumar and Reardon, {Hue V.} and Mudunuri, {Uma S.} and Collins, {Jack R.} and Sushma Nagaraj and Vineela Gangalapudi and Manoj Tyagi and Zhu, {Yuelin J.} and Masih, {Katherine E.} and Yohe, {Marielle E.} and Shern, {Jack F.} and Yue Qi and Udayan Guha and Daniel Catchpoole and Orentas, {Rimas J.} and Kuznetsov, {Igor B.} and Llosa, {Nicolas J.} and Ligon, {John A.} and Turpin, {Brian K.} and Leino, {Daniel G.} and Shintaro Iwata and Andrulis, {Irene L.} and Wunder, {Jay S.} and Toledo, {Silvia R.C.} and Meltzer, {Paul S.} and Ching Lau and Teicher, {Beverly A.} and Heather Magnan and Marc Ladanyi and Javed Khan",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = nov,

day = "23",

doi = "10.1016/j.celrep.2021.110047",

language = "English (US)",

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T1 - Immuno-transcriptomic profiling of extracranial pediatric solid malignancies

AU - Brohl, Andrew S.

AU - Sindiri, Sivasish

AU - Wei, Jun S.

AU - Milewski, David

AU - Chou, Hsien Chao

AU - Song, Young K.

AU - Wen, Xinyu

AU - Kumar, Jeetendra

AU - Reardon, Hue V.

AU - Mudunuri, Uma S.

AU - Collins, Jack R.

AU - Nagaraj, Sushma

AU - Gangalapudi, Vineela

AU - Tyagi, Manoj

AU - Zhu, Yuelin J.

AU - Masih, Katherine E.

AU - Yohe, Marielle E.

AU - Shern, Jack F.

AU - Qi, Yue

AU - Guha, Udayan

AU - Catchpoole, Daniel

AU - Orentas, Rimas J.

AU - Kuznetsov, Igor B.

AU - Llosa, Nicolas J.

AU - Ligon, John A.

AU - Turpin, Brian K.

AU - Leino, Daniel G.

AU - Iwata, Shintaro

AU - Andrulis, Irene L.

AU - Wunder, Jay S.

AU - Toledo, Silvia R.C.

AU - Meltzer, Paul S.

AU - Lau, Ching

AU - Teicher, Beverly A.

AU - Magnan, Heather

AU - Ladanyi, Marc

AU - Khan, Javed

PY - 2021/11/23

Y1 - 2021/11/23

N2 - We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

AB - We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

KW - PRAME

KW - RNA sequencing

KW - T cell receptor

KW - adoptive cell therapy

KW - immunogenomics

KW - immunopeptidomics

KW - pediatric oncology

KW - tumor-infiltrating lymphocytes

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U2 - 10.1016/j.celrep.2021.110047

DO - 10.1016/j.celrep.2021.110047

M3 - Article

C2 - 34818552

AN - SCOPUS:85119484764

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 110047

ER -

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies

Abstract

Keywords

ASJC Scopus subject areas

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