Dynamics of genomic and immune responses during primary immunotherapy resistance in mismatch repair-deficient tumors.
neoplasm of the lung
Journal
Cold Spring Harbor molecular case studies
ISSN: 2373-2873
Titre abrégé: Cold Spring Harb Mol Case Stud
Pays: United States
ID NLM: 101660017
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
11
06
2020
accepted:
10
08
2020
entrez:
8
10
2020
pubmed:
9
10
2020
medline:
5
6
2021
Statut:
epublish
Résumé
Mismatch repair-deficient (dMMR) cancers generate a substantial number of immunogenic neoantigens, rendering them sensitive to immunotherapy. Yet, there is considerable variability in responses, and roughly one-half of dMMR cancers are refractory to immunotherapy. Here we study a patient with dMMR lung cancer refractory to immunotherapy. The tumor exhibited typical dMMR molecular features, including exceptionally high frameshift insertions and deletions (indels). Despite the treatment inducing abundant intratumoral T-cell infiltrates, it failed to elicit tumor regression, pointing to the T cells lacking cytotoxic activity. A post-treatment tumor demonstrated compound heterozygous frameshift deletions located upstream of the kinase domain in the gene encoding JAK1 protein, down-regulation of JAK1 and mediators of its signal transduction, and total loss of JAK1 phosphorylation. Importantly, one of the
Identifiants
pubmed: 33028646
pii: mcs.a005678
doi: 10.1101/mcs.a005678
pmc: PMC7552928
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
MLH1 protein, human
0
JAK1 protein, human
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
MutL Protein Homolog 1
EC 3.6.1.3
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2020 Takahashi et al.; Published by Cold Spring Harbor Laboratory Press.
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