Decreased local immune response and retained HPV gene expression during chemoradiotherapy are associated with treatment resistance and death from cervical cancer.
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Biopsy
Combined Modality Therapy
Drug Resistance, Neoplasm
/ immunology
Female
Gene Expression Profiling
Gene Expression Regulation, Viral
Humans
Immunomodulation
/ drug effects
Lymphatic Metastasis
Neoplasm Staging
Papillomaviridae
/ classification
Papillomavirus Infections
/ complications
Prognosis
T-Lymphocyte Subsets
/ immunology
Uterine Cervical Neoplasms
/ diagnosis
HPV
cervical cancer
immune response
lymphocyte
radiation therapy
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
received:
03
04
2019
accepted:
28
10
2019
pubmed:
17
11
2019
medline:
20
2
2020
entrez:
17
11
2019
Statut:
ppublish
Résumé
More than one-third of patients with locally advanced cervical cancer do not respond to chemoradiation therapy (CRT). We aimed to characterize the transcriptional landscape of paired human cervical tumors before and during CRT in order to gain insight into the evolution of treatment response and to elucidate mechanisms of treatment resistance. We prospectively collected cervical tumor biopsies from 115 patients both before and 3 weeks into CRT. RNA-sequencing, Gene Set Enrichment Analysis and HPV gene expression were performed on 20 paired samples that had adequate neoplastic tissue mid-treatment. Tumors from patients with no evidence of disease (NED) at last follow-up had enrichment in pathways related to the immune response both pretreatment and mid-treatment, while tumors from patients dead of disease (DOD) demonstrated enrichment in biosynthetic and mitotic pathways but not in immune-related pathways. Patients DOD had decreased expression of T-cell and cytolytic genes and increased expression of PD-L2 mid-treatment compared to patients NED. Histological and immunohistochemical analysis revealed a decrease in tumor-associated lymphocytes (TAL) during CRT in all patients but tumors from patients DOD had a significantly more pronounced decrease in TALs and CD8+ cells mid-treatment, which was validated in a larger mid-treatment cohort. Finally, patients DOD retained more HPV E6/E7 gene expression during CRT and this was associated with increased expression of genes driving mitosis, which was corroborated in vitro. Our results suggest that decreased local immune response and retained HPV gene expression may be acting together to promote treatment resistance during CRT in patients with cervical cancer.
Identifiants
pubmed: 31732968
doi: 10.1002/ijc.32793
pmc: PMC8177718
mid: NIHMS1704245
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2047-2058Subventions
Organisme : NIH HHS
ID : R01GM089784
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE026471
Pays : United States
Organisme : NIH HHS
ID : R01DE026471
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181745
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM089784
Pays : United States
Organisme : NCI NIH HHS
ID : R25 CA190190
Pays : United States
Informations de copyright
© 2019 UICC.
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