Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors

International Journal of Molecular Sciences

Anna Skorska¹  Heiko Lemcke¹  Leonie Engster²  Inken Salewski²  Julia Henne²  Claudia Maletzki²  Christian Junghanss²  Larissa Henze²  Peggy Berlin³  Bjoern Schneider⁴ 

[1] Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany;Department of Medicine, Clinic III–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany;Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany;Institute of Pathology, Rostock University Medical Center, University of Rostock, 18057 Rostock, Germany;

关键词: immune checkpoint inhibitor;    MMR deficiency;    in vivo imaging;    tumor microenvironment;    genetic model;    coding microsatellite mutations;   

DOI  :  10.3390/ijms22115990

来源: DOAJ

【 摘 要 】

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; 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.

【 授权许可】

Unknown