Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

Samuel S. Freeman; Moshe Sade-Feldman; Jaegil Kim; Chip Stewart; Anna L.K. Gonye; Arvind Ravi; Monica B. Arniella; Irena Gushterova; Thomas J. LaSalle; Emily M. Blaum; Keren Yizhak; Dennie T. Frederick; Tatyana Sharova; Ignaty Leshchiner; Liudmila Elagina; Oliver G. Spiro; Dimitri Livitz; Daniel Rosebrock; François Aguet; Jian Carrot-Zhang; Gavin Ha; Ziao Lin; Jonathan H. Chen; Michal Barzily-Rokni; Marc R. Hammond; Hans C. Vitzthum von Eckstaedt; Shauna M. Blackmon; Yunxin J. Jiao; Stacey Gabriel; Donald P. Lawrence; Lyn M. Duncan; Anat O. Stemmer-Rachamimov; Jennifer A. Wargo; Keith T. Flaherty; Ryan J. Sullivan; Genevieve M. Boland; Matthew Meyerson; Gad Getz; Nir Hacohen

doi:10.1016/j.xcrm.2021.100500

Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

Samuel S. Freeman
, Moshe Sade-Feldman
, Jaegil Kim
, Chip Stewart
, Anna L.K. Gonye
, Arvind Ravi
, Monica B. Arniella
, Irena Gushterova
, Thomas J. LaSalle
, Emily M. Blaum
, Keren Yizhak
, Dennie T. Frederick
, Tatyana Sharova
, Ignaty Leshchiner
, Liudmila Elagina
, Oliver G. Spiro
, Dimitri Livitz
, Daniel Rosebrock
, François Aguet
, Jian Carrot-Zhang

Gavin Ha, Ziao Lin, Jonathan H. Chen, Michal Barzily-Rokni, Marc R. Hammond, Hans C. Vitzthum von Eckstaedt, Shauna M. Blackmon, Yunxin J. Jiao, Stacey Gabriel, Donald P. Lawrence, Lyn M. Duncan, Anat O. Stemmer-Rachamimov, Jennifer A. Wargo, Keith T. Flaherty, Ryan J. Sullivan, Genevieve M. Boland, Matthew Meyerson, Gad Getz, Nir Hacohen

Medicine

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

Abstract

Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMB^high and TCB^high or BCB^high have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.

Original language	English
Article number	100500
Pages (from-to)	100500
Journal	Cell Reports Medicine
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2021.100500
State	Published - 15 Feb 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

cancer genomics
cancer immunotherapy
immune checkpoint blockade
integrative model
melanoma
melanoma subtype
T cell receptor
TMB
tumor mutational burden
RNA
Humans
Transcriptome/genetics
Whole Exome Sequencing
Sequence Analysis, RNA
Melanoma/drug therapy
Exome Sequencing

ASJC Scopus subject areas

General Medicine
General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2021.100500

Cite this

Freeman, S. S., Sade-Feldman, M., Kim, J., Stewart, C., Gonye, A. L. K., Ravi, A., Arniella, M. B., Gushterova, I., LaSalle, T. J., Blaum, E. M., Yizhak, K., Frederick, D. T., Sharova, T., Leshchiner, I., Elagina, L., Spiro, O. G., Livitz, D., Rosebrock, D., Aguet, F., ... Hacohen, N. (2022). Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma. Cell Reports Medicine, 3(2), 100500. Article 100500. https://doi.org/10.1016/j.xcrm.2021.100500

@article{ede05a807dcd48a6ba56eccd88e2b2f1,

title = "Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma",

abstract = "Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMBhigh and TCBhigh or BCBhigh have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.",

keywords = "cancer genomics, cancer immunotherapy, immune checkpoint blockade, integrative model, melanoma, melanoma subtype, T cell receptor, TMB, tumor mutational burden, RNA, Humans, Transcriptome/genetics, Whole Exome Sequencing, Sequence Analysis, RNA, Melanoma/drug therapy, Exome Sequencing",

author = "Freeman, \{Samuel S.\} and Moshe Sade-Feldman and Jaegil Kim and Chip Stewart and Gonye, \{Anna L.K.\} and Arvind Ravi and Arniella, \{Monica B.\} and Irena Gushterova and LaSalle, \{Thomas J.\} and Blaum, \{Emily M.\} and Keren Yizhak and Frederick, \{Dennie T.\} and Tatyana Sharova and Ignaty Leshchiner and Liudmila Elagina and Spiro, \{Oliver G.\} and Dimitri Livitz and Daniel Rosebrock and Fran{\c c}ois Aguet and Jian Carrot-Zhang and Gavin Ha and Ziao Lin and Chen, \{Jonathan H.\} and Michal Barzily-Rokni and Hammond, \{Marc R.\} and \{Vitzthum von Eckstaedt\}, \{Hans C.\} and Blackmon, \{Shauna M.\} and Jiao, \{Yunxin J.\} and Stacey Gabriel and Lawrence, \{Donald P.\} and Duncan, \{Lyn M.\} and Stemmer-Rachamimov, \{Anat O.\} and Wargo, \{Jennifer A.\} and Flaherty, \{Keith T.\} and Sullivan, \{Ryan J.\} and Boland, \{Genevieve M.\} and Matthew Meyerson and Gad Getz and Nir Hacohen",

note = "{\textcopyright} 2021 The Author(s).",

year = "2022",

month = feb,

day = "15",

doi = "10.1016/j.xcrm.2021.100500",

language = "אנגלית",

volume = "3",

pages = "100500",

number = "2",

}

Freeman, SS, Sade-Feldman, M, Kim, J, Stewart, C, Gonye, ALK, Ravi, A, Arniella, MB, Gushterova, I, LaSalle, TJ, Blaum, EM, Yizhak, K, Frederick, DT, Sharova, T, Leshchiner, I, Elagina, L, Spiro, OG, Livitz, D, Rosebrock, D, Aguet, F, Carrot-Zhang, J, Ha, G, Lin, Z, Chen, JH, Barzily-Rokni, M, Hammond, MR, Vitzthum von Eckstaedt, HC, Blackmon, SM, Jiao, YJ, Gabriel, S, Lawrence, DP, Duncan, LM, Stemmer-Rachamimov, AO, Wargo, JA, Flaherty, KT, Sullivan, RJ, Boland, GM, Meyerson, M, Getz, G & Hacohen, N 2022, 'Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma', Cell Reports Medicine, vol. 3, no. 2, 100500, pp. 100500. https://doi.org/10.1016/j.xcrm.2021.100500

TY - JOUR

T1 - Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

AU - Freeman, Samuel S.

AU - Sade-Feldman, Moshe

AU - Kim, Jaegil

AU - Stewart, Chip

AU - Gonye, Anna L.K.

AU - Ravi, Arvind

AU - Arniella, Monica B.

AU - Gushterova, Irena

AU - LaSalle, Thomas J.

AU - Blaum, Emily M.

AU - Yizhak, Keren

AU - Frederick, Dennie T.

AU - Sharova, Tatyana

AU - Leshchiner, Ignaty

AU - Elagina, Liudmila

AU - Spiro, Oliver G.

AU - Livitz, Dimitri

AU - Rosebrock, Daniel

AU - Aguet, François

AU - Carrot-Zhang, Jian

AU - Ha, Gavin

AU - Lin, Ziao

AU - Chen, Jonathan H.

AU - Barzily-Rokni, Michal

AU - Hammond, Marc R.

AU - Vitzthum von Eckstaedt, Hans C.

AU - Blackmon, Shauna M.

AU - Jiao, Yunxin J.

AU - Gabriel, Stacey

AU - Lawrence, Donald P.

AU - Duncan, Lyn M.

AU - Stemmer-Rachamimov, Anat O.

AU - Wargo, Jennifer A.

AU - Flaherty, Keith T.

AU - Sullivan, Ryan J.

AU - Boland, Genevieve M.

AU - Meyerson, Matthew

AU - Getz, Gad

AU - Hacohen, Nir

PY - 2022/2/15

Y1 - 2022/2/15

N2 - Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMBhigh and TCBhigh or BCBhigh have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.

AB - Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains underexplored. Here, we analyze whole-exome and bulk RNA sequencing of tumors from new and published cohorts of 189 and 178 patients with melanoma receiving CPB, respectively. Using DNA, we calculate T cell and B cell burdens (TCB/BCB) from rearranged TCR/Ig sequences and find that patients with TMBhigh and TCBhigh or BCBhigh have improved outcomes compared to other patients. By combining pairs of immune- and tumor-expressed genes, we identify three gene pairs associated with response and survival, which validate in independent cohorts. The top model includes lymphocyte-expressed MAP4K1 and tumor-expressed TBX3. Overall, RNA or DNA-based models combining immune and tumor measures improve predictions of melanoma CPB outcomes.

KW - cancer genomics

KW - cancer immunotherapy

KW - immune checkpoint blockade

KW - integrative model

KW - melanoma

KW - melanoma subtype

KW - T cell receptor

KW - TMB

KW - tumor mutational burden

KW - RNA

KW - Humans

KW - Transcriptome/genetics

KW - Whole Exome Sequencing

KW - Sequence Analysis, RNA

KW - Melanoma/drug therapy

KW - Exome Sequencing

UR - https://www.scopus.com/pages/publications/85124612851

U2 - 10.1016/j.xcrm.2021.100500

DO - 10.1016/j.xcrm.2021.100500

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 35243413

AN - SCOPUS:85124612851

VL - 3

SP - 100500

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 2

M1 - 100500

ER -

Combined tumor and immune signals from genomes or transcriptomes predict outcomes of checkpoint inhibition in melanoma

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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