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Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer.

ABSTRACT: BACKGROUND:Mismatch Repair Deficiency (MMR-D)-related tumors are highly immunogenic and constitute ideal vaccination targets. In a proof-of-concept study delayed tumorigenesis and prolonged survival has been shown in a clinically-relevant mouse model for MMR-D-related diseases (=MLH1 knock out mice). To refine this approach, vaccination was combined with immune modulatory low-dose chemotherapy to polarize immune regulatory subtypes. METHODS:Mice (prophylactic: 8-10?weeks; therapeutic: >?36?weeks) received a single injection of cyclophosphamide (CPX, 120?mg/kg bw, i.p.) or gemcitabine (GEM, 100?mg/kg bw, i.p.) prior to vaccination (lysate of a gastrointestinal tumor allograft, 10?mg/kg bw, n?=?9 mice/group). The vaccine was given repetitively (10?mg/kg bw, s.c., 4 x / once a week, followed by monthly boosts) until tumor formation or progression. Tumor growth ([18F] FDG PET/CT imaging) and immune responses were monitored (flow cytometry, IFN? ELISpot). The microenvironment was analyzed by immunofluorescence. RESULTS:Prophylactic application of GEM + lysate delayed tumorigenesis compared to lysate monotherapy and CPX-pre-treatment (median time of onset: 53 vs. 47 vs. 48?weeks). 33% of mice even remained tumor-free until the experimental endpoint (= 65?weeks). This was accompanied by long-term effect on cytokine plasma levels; splenic myeloid derived suppressor cells (MDSC) as well as regulatory T cell numbers. Assessment of tumor microenvironment from GEM + lysate treated mice revealed low numbers of MDSCs, but enhanced T cell infiltration, in some cases co-expressing PD-L1. Therapeutic chemo-immunotherapy (GEM + lysate) had minor impact on overall survival (median time: 12 (GEM + lysate) vs. 11.5 (lysate) vs. 3?weeks (control)), but induced complete remission in one case. Dendritic and T cell infiltrates increased in both treatment groups. Reactive T cells specifically recognized MLH1-/- tumor cells in IFN? ELISpot, but lacked response towards NK cell targets YAC-1. CONCLUSIONS:Combined chemo-immunotherapy impairs tumor onset and growth likely attributable to modulation of immune responses. Depleting or 're-educating' immunosuppressive cell types, such as MDSC, may help moving a step closer to combat cancer.

SUBMITTER: Maletzki C

PROVIDER: S-EPMC6329128 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer.

Maletzki Claudia C Wiegele Leonie L Nassar Ingy I Stenzel Jan J Junghanss Christian C

Journal for immunotherapy of cancer 20190110 1

<h4>Background</h4>Mismatch Repair Deficiency (MMR-D)-related tumors are highly immunogenic and constitute ideal vaccination targets. In a proof-of-concept study delayed tumorigenesis and prolonged survival has been shown in a clinically-relevant mouse model for MMR-D-related diseases (=MLH1 knock out mice). To refine this approach, vaccination was combined with immune modulatory low-dose chemotherapy to polarize immune regulatory subtypes.<h4>Methods</h4>Mice (prophylactic: 8-10 weeks; therapeu ...[more]

PMID: 30630527

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Project description:Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-y) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-B (AB) deposition and tau pathology was treated with the TZD pioglitazone (PIO- Actos) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal AB deposits, and enhanced short- and long-term plasticity. Baseline electrophysiological membrane properties and blood glucose levels were unchanged by PIO treatment. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes, and decreases in glutamatergic and ketone metabolic/ cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. Keywords : Hippocampus; LTP; Microarray analysis; Avoidance learning; Aging; PPAR; Synaptic hyperpolarization; T2DM We used the 3xTg-AD mouse model of Alzheimer's disease and monitored the effects of pioglitazone (PIO-Actos a TZD) on behavioral, electrophysiological, and molecular variables. Emphasis was placed on identifying hippocampal PIO-sensitive genes that were also associated with learning and memory processes. Starting at 10 months of age, female mice were treated for approximately 14 weeks with either a control diet or a PIO-containing diet. PIO was incorporated into the diet to yield a final dose of approximately 18 mg/kg body weight/day.

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Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer.

Publications

Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer.

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