Modulation of temozolomide dose differentially affects T-cell response to immune checkpoint inhibition.
Animals
Antibodies, Monoclonal
/ pharmacology
Antineoplastic Agents, Alkylating
/ pharmacology
Brain Neoplasms
/ drug therapy
Dose-Response Relationship, Drug
Drug Therapy, Combination
Glioblastoma
/ drug therapy
Humans
Immunotherapy
Lymphocytes, Tumor-Infiltrating
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Transgenic
Programmed Cell Death 1 Receptor
/ immunology
T-Lymphocytes
/ drug effects
Temozolomide
/ pharmacology
Tumor Cells, Cultured
Tumor Microenvironment
PD-1 antibody
glioblastoma
immune checkpoint inhibition
immunomodulation
temozolomide
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
10 06 2019
10 06 2019
Historique:
pubmed:
23
1
2019
medline:
1
7
2020
entrez:
23
1
2019
Statut:
ppublish
Résumé
The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM. Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models. SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone. The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.
Sections du résumé
BACKGROUND
The changes induced in host immunity and the tumor microenvironment by chemotherapy have been shown to impact immunotherapy response in both a positive and a negative fashion. Temozolomide is the most common chemotherapy used to treat glioblastoma (GBM) and has been shown to have variable effects on immune response to immunotherapy. Therefore, we aimed to determine the immune modulatory effects of temozolomide that would impact response to immune checkpoint inhibition in the treatment of experimental GBM.
METHODS
Immune function and antitumor efficacy of immune checkpoint inhibition were tested after treatment with metronomic dose (MD) temozolomide (25 mg/kg × 10 days) or standard dose (SD) temozolomide (50 mg/kg × 5 days) in the GL261 and KR158 murine glioma models.
RESULTS
SD temozolomide treatment resulted in an upregulation of markers of T-cell exhaustion such as LAG-3 and TIM-3 in lymphocytes which was not seen with MD temozolomide. When temozolomide treatment was combined with programmed cell death 1 (PD-1) antibody therapy, the MD temozolomide/PD-1 antibody group demonstrated a decrease in exhaustion markers in tumor infiltrating lymphocytes that was not observed in the SD temozolomide/PD-1 antibody group. Also, the survival advantage of PD-1 antibody therapy in a murine syngeneic intracranial glioma model was abrogated by adding SD temozolomide to treatment. However, when MD temozolomide was added to PD-1 inhibition, it preserved the survival benefit that was seen by PD-1 antibody therapy alone.
CONCLUSION
The peripheral and intratumoral immune microenvironments are distinctively affected by dose modulation of temozolomide.
Identifiants
pubmed: 30668768
pii: 5298911
doi: 10.1093/neuonc/noz015
pmc: PMC6556847
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antineoplastic Agents, Alkylating
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
730-741Subventions
Organisme : NINDS NIH HHS
ID : K08 NS099484
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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