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
N1 - © 2021 The Author(s).
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 - http://www.scopus.com/inward/record.url?scp=85124612851&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2021.100500
DO - 10.1016/j.xcrm.2021.100500
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C2 - 35243413
AN - SCOPUS:85124612851
VL - 3
SP - 100500
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 2
M1 - 100500
ER -