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Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors
- Source :
- International Journal of Molecular Sciences, Vol 22, Iss 5990, p 5990 (2021), International Journal of Molecular Sciences, Volume 22, Issue 11
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1−/− mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11<br />2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1−/−-tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1−/− mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1β were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.
- Subjects :
- QH301-705.5
immune checkpoint inhibitor
DNA Mismatch Repair
Deoxycytidine
Article
B7-H1 Antigen
Mice
Lymphocytes, Tumor-Infiltrating
Neoplastic Syndromes, Hereditary
Animals
Humans
tumor microenvironment
Biology (General)
Chemokine CCL4
Immune Checkpoint Inhibitors
QD1-999
coding microsatellite mutations
Interleukin-13
Brain Neoplasms
Tumor Necrosis Factor-alpha
Myeloid-Derived Suppressor Cells
MMR deficiency
Colorectal Neoplasms, Hereditary Nonpolyposis
Gemcitabine
Disease Models, Animal
Chemistry
Drug Resistance, Neoplasm
genetic model
in vivo imaging
Colorectal Neoplasms
MutL Protein Homolog 1
T-Lymphocytes, Cytotoxic
Subjects
Details
- Language :
- English
- ISSN :
- 16616596 and 14220067
- Volume :
- 22
- Issue :
- 5990
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.pmid.dedup....d6a50fa74e0660d3fae61118086ab50d