Abstract
In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
| Original language | English (US) |
|---|---|
| Article number | 100139 |
| Journal | Cell Reports Medicine |
| Volume | 1 |
| Issue number | 8 |
| DOIs | |
| State | Published - Nov 17 2020 |
Keywords
- T cell repertoire
- cancer genomics
- immune checkpoint blockade
- integrative predictive model
- melanoma
- multi-omics
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
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Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma. / Anagnostou, Valsamo; Bruhm, Daniel C.; Niknafs, Noushin; White, James R.; Shao, Xiaoshan M.; Sidhom, John William; Stein, Julie; Tsai, Hua Ling; Wang, Hao; Belcaid, Zineb; Murray, Joseph; Balan, Archana; Ferreira, Leonardo; Ross-Macdonald, Petra; Wind-Rotolo, Megan; Baras, Alexander S.; Taube, Janis; Karchin, Rachel; Scharpf, Robert B.; Grasso, Catherine; Ribas, Antoni; Pardoll, Drew M.; Topalian, Suzanne L.; Velculescu, Victor E.
In: Cell Reports Medicine, Vol. 1, No. 8, 100139, 17.11.2020.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma
AU - Anagnostou, Valsamo
AU - Bruhm, Daniel C.
AU - Niknafs, Noushin
AU - White, James R.
AU - Shao, Xiaoshan M.
AU - Sidhom, John William
AU - Stein, Julie
AU - Tsai, Hua Ling
AU - Wang, Hao
AU - Belcaid, Zineb
AU - Murray, Joseph
AU - Balan, Archana
AU - Ferreira, Leonardo
AU - Ross-Macdonald, Petra
AU - Wind-Rotolo, Megan
AU - Baras, Alexander S.
AU - Taube, Janis
AU - Karchin, Rachel
AU - Scharpf, Robert B.
AU - Grasso, Catherine
AU - Ribas, Antoni
AU - Pardoll, Drew M.
AU - Topalian, Suzanne L.
AU - Velculescu, Victor E.
N1 - Funding Information: We thank members of our labs for critical review of the manuscript. This work was supported by Bristol-Myers Squibb and in part by US National Institutes of Health grants CA121113 (V.E.V. and V.A.), CA233259 (V.E.V.), CA006973 (V.E.V.), CA142779 (S.L.T., J.T., and D.P.M.) and CA233259 (V.E.V.); the Commonwealth Foundation (V.E.V.); the Bloomberg-Kimmel Institute for Cancer Immunotherapy (V.A., J.T., D.M.P., S.L.T., and V.E.V.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (V.E.V.); the V Foundation (V.A. and V.E.V.); Swim Across America (V.A.); the Allegheny Health Network – Johns Hopkins Research Fund (V.A. and V.E.V.); the LUNGevity Foundation (V.A.); the Mark Foundation For Cancer Research (V.E.V. and J.T.); the Barney Foundation (J.T. and S.L.T.); Moving for Melanoma of Delaware (J.T. and S.L.T.); the Laverna Hahn Charitable Trust (J.T. and S.L.T.); the Melanoma Research Alliance (J.T., A.R., D.M.P., and S.L.T.); and a Cancer Immunology Translational Cancer Research Grant ( SU2C-AACR-DT1012 ) from Cancer Research Institute–Stand Up 2 Cancer (J.T., A.R., D.M.P., and S.L.T.). Stand Up 2 Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Funding Information: V.A. and J.T. receive research funding from Bristol-Myers Squibb. J.T. serves as a consultant/advisory board member to Bristol-Myers Squibb, Merck, Astra Zeneca, and Compugen. J.R.W. is a consultant for Personal Genome Diagnostics; is the founder and owner of Resphera Biosciences; and holds patents, royalties, or other intellectual property from Personal Genomic Diagnostics. A.B. receives honoraria from Proscia and Corista; is a consultant of Bristol-Myers Squibb, Genentech, and Bayer; and receives research funding from Genentech. C.G. has patents, royalties, or other intellectual property from Karyopharm and Arcus. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi; is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics; and has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C). P.R.-M. and M.W.-R. are employees of Bristol-Myers Squibb. D.M.P. and S.L.T. report stock and other ownership interests in Aduro Biotech, DNAtrix, Dracen Pharmaceuticals, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, Potenza Therapeutics, RAPT, Tizona Therapeutics, Trieza Therapeutics, and WindMIL; a consulting or advisory role in Amgen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, Immunocore, Immunomic Therapeutics, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Merck, RAPT, and WindMIL; research grants from Bristol-Myers Squibb and Compugen; patents, royalties, and/or other intellectual property through their institution with Aduro Biotech, Arbor Pharmaceuticals, Bristol-Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL; and travel, accommodations, and expenses from Bristol-Myers Squibb and Five Prime Therapeutics. V.E.V. is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. V.E.V. is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals. Within the last 5 years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Funding Information: We thank members of our labs for critical review of the manuscript. This work was supported by Bristol-Myers Squibb and in part by US National Institutes of Health grants CA121113 (V.E.V. and V.A.), CA233259 (V.E.V.), CA006973 (V.E.V.), CA142779 (S.L.T. J.T. and D.P.M.) and CA233259 (V.E.V.); the Commonwealth Foundation (V.E.V.); the Bloomberg-Kimmel Institute for Cancer Immunotherapy (V.A. J.T. D.M.P. S.L.T. and V.E.V.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (V.E.V.); the V Foundation (V.A. and V.E.V.); Swim Across America (V.A.); the Allegheny Health Network ? Johns Hopkins Research Fund (V.A. and V.E.V.); the LUNGevity Foundation (V.A.); the Mark Foundation For Cancer Research (V.E.V. and J.T.); the Barney Foundation (J.T. and S.L.T.); Moving for Melanoma of Delaware (J.T. and S.L.T.); the Laverna Hahn Charitable Trust (J.T. and S.L.T.); the Melanoma Research Alliance (J.T. A.R. D.M.P. and S.L.T.); and a Cancer Immunology Translational Cancer Research Grant (SU2C-AACR-DT1012) from Cancer Research Institute?Stand Up 2 Cancer (J.T. A.R. D.M.P. and S.L.T.). Stand Up 2 Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Conceptualization, V.A. S.L.T. and V.E.V.; Methodology, V.A. D.C.B. N.N. J.R.W. X.M.S. and V.E.V.; Software, D.C.B. N.N. J.R.W. X.M.S. and A.B.; Formal Analysis, V.A. D.C.B. N.N. J.R.W. A.B. L.F. R.K. and R.B.S.; Resources, P.R.-M. and M.W.-R.; Data Curation, P.R.-M. and M.W.-R.; Writing ? Original Draft, V.A. D.C.B. J.W.S. Z.B. J.M. A.S.B. C.G. A.R. D.M.P. S.L.T. and V.E.V.; Visualization, V.A. D.C.B. N.N. and J.R.W.; Supervision, V.A. S.L.T. and V.E.V.; Funding Acquisition, V.A. S.L.T. and V.E.V. V.A. and J.T. receive research funding from Bristol-Myers Squibb. J.T. serves as a consultant/advisory board member to Bristol-Myers Squibb, Merck, Astra Zeneca, and Compugen. J.R.W. is a consultant for Personal Genome Diagnostics; is the founder and owner of Resphera Biosciences; and holds patents, royalties, or other intellectual property from Personal Genomic Diagnostics. A.B. receives honoraria from Proscia and Corista; is a consultant of Bristol-Myers Squibb, Genentech, and Bayer; and receives research funding from Genentech. C.G. has patents, royalties, or other intellectual property from Karyopharm and Arcus. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi; is or has been a member of the scientific advisory board and holds stock in Advaxis, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics; and has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C). P.R.-M. and M.W.-R. are employees of Bristol-Myers Squibb. D.M.P. and S.L.T. report stock and other ownership interests in Aduro Biotech, DNAtrix, Dracen Pharmaceuticals, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, Potenza Therapeutics, RAPT, Tizona Therapeutics, Trieza Therapeutics, and WindMIL; a consulting or advisory role in Amgen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, Immunocore, Immunomic Therapeutics, Janssen Pharmaceuticals, MedImmune/AstraZeneca, Merck, RAPT, and WindMIL; research grants from Bristol-Myers Squibb and Compugen; patents, royalties, and/or other intellectual property through their institution with Aduro Biotech, Arbor Pharmaceuticals, Bristol-Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL; and travel, accommodations, and expenses from Bristol-Myers Squibb and Five Prime Therapeutics. V.E.V. is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. V.E.V. is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals. Within the last 5 years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Publisher Copyright: © 2020 The Authors
PY - 2020/11/17
Y1 - 2020/11/17
N2 - In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
AB - In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
KW - T cell repertoire
KW - cancer genomics
KW - immune checkpoint blockade
KW - integrative predictive model
KW - melanoma
KW - multi-omics
UR - http://www.scopus.com/inward/record.url?scp=85096957269&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096957269&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2020.100139
DO - 10.1016/j.xcrm.2020.100139
M3 - Article
C2 - 33294860
AN - SCOPUS:85096957269
VL - 1
JO - Cell Reports Medicine
JF - Cell Reports Medicine
SN - 2666-3791
IS - 8
M1 - 100139
ER -