Integrated transcriptional-phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients.
Aged
Angiogenesis Inhibitors
/ therapeutic use
Biomarkers, Tumor
/ genetics
Carcinoma, Renal Cell
/ drug therapy
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Immunomodulation
Indazoles
/ therapeutic use
Kidney Neoplasms
/ drug therapy
Male
Myeloid-Derived Suppressor Cells
/ immunology
Prognosis
Pyrimidines
/ therapeutic use
Sulfonamides
/ therapeutic use
Survival Rate
Transcriptome
Tumor Cells, Cultured
Tumor Microenvironment
antiangiogenics
bioinformatics
blood transcriptomic profile
cancer biomarkers
immunomonitoring
immunosuppression
immunotherapy
myeloid-derived suppressor cells
pazopanib
renal cell carcinoma
transcriptional modular repertoire analysis
tyrosine kinase inhibitors
Journal
Clinical and translational medicine
ISSN: 2001-1326
Titre abrégé: Clin Transl Med
Pays: United States
ID NLM: 101597971
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
09
05
2021
received:
15
09
2020
accepted:
12
05
2021
entrez:
29
6
2021
pubmed:
30
6
2021
medline:
9
2
2022
Statut:
ppublish
Résumé
The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms. We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14 Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells. The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
Sections du résumé
BACKGROUND
The combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms.
METHODS
We used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid-derived suppressor (MDSC)-like cells were generated from CD14
RESULTS
Pazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD-1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune-effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC-mediated suppression, rather than a direct effect on NK and T cells.
CONCLUSIONS
The marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
Identifiants
pubmed: 34185403
doi: 10.1002/ctm2.434
pmc: PMC8214860
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Biomarkers, Tumor
0
Indazoles
0
Pyrimidines
0
Sulfonamides
0
pazopanib
7RN5DR86CK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e434Informations de copyright
© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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