Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity.
Antibodies, Monoclonal, Humanized
/ therapeutic use
Antineoplastic Agents
/ therapeutic use
BRCA2 Protein
/ genetics
Circulating Tumor DNA
/ genetics
DNA Copy Number Variations
Drug Resistance, Neoplasm
Group II Phospholipases A2
/ genetics
Humans
Neoplasms
/ drug therapy
Prospective Studies
Tumor Burden
Tumor Escape
/ drug effects
Exome Sequencing
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 08 2021
26 08 2021
Historique:
received:
09
10
2020
accepted:
06
08
2021
entrez:
27
8
2021
pubmed:
28
8
2021
medline:
23
9
2021
Statut:
epublish
Résumé
Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
Identifiants
pubmed: 34446728
doi: 10.1038/s41467-021-25432-7
pii: 10.1038/s41467-021-25432-7
pmc: PMC8390680
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents
0
BRCA2 Protein
0
BRCA2 protein, human
0
Circulating Tumor DNA
0
pembrolizumab
DPT0O3T46P
Group II Phospholipases A2
EC 3.1.1.4
PLA2G2D protein, human
EC 3.1.1.4
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5137Informations de copyright
© 2021. The Author(s).
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