Table 1.
Overview on similarities and disparities between Mlh1−/− and Msh2loxP/loxP Villin Cre mice
| Characteristic | Mlh1−/− | Msh2loxP/loxP Villin Cre | ||
|---|---|---|---|---|
| Strain specificity and model establishment | Mouse | Mouse strain | C57Bl/6 | C57Bl/6 |
| Type of knock out | Constitutional | Conditional, gut | ||
| Spontaneous tumor formation | Yes | Yes | ||
| Clinicopathological characteristics | Human | Frequency of the underlying MMR defect in human | ~35 % | ~ 40% |
| Human disease counterpart | Lynch syndrome and constitutional mismatch repair deficiency | Lynch syndrome | ||
| Human lifetime risk of tumorigenesis | ♂: 27 – 74 % | ♂: 27 – 74 % | ||
| ♀: 22 – 53 % | ♀: 22 – 53 % | |||
| Mouse | Murine mean age of onset | 26 weeks (lymphoma), 35 weeks (GIT) | 35 weeks (GIT) | |
| Tumor penetrance | High, >90 % | High, >95 % | ||
| Tumor spectrum | LS-associated tumors ≥ hematological malignancies (lymphoma) > others (skin) | LS-associated tumors | ||
| Manifestation | Jejunum | Jejunum | ||
| Metastastic spread | Not in GIT, lymphomas: yes | No | ||
| MHC class I expression | 100% positive | 100% positive | ||
| MSI in mononucleotide repeats | High | High | ||
| MSI in coding mononucleotide repeats | Low | High | ||
| Tumor microenvironment | Mouse | Cytotoxic T-cells | Low | Moderate |
| T helper cells | Low | Low | ||
| MDSC | Moderate | Moderate | ||
| TAM | Moderate | High | ||
| PD-L1 | Low | Moderate | ||
| Treatment response towards | Immune checkpoint inhibition (α-PD-L1) | Poor > moderate | Moderate | |
| CDK4/6 inhibition | Good | Good | ||
| Combined ICI/CDKI | Missing | Missing | ||
| Immunological effects upon CDKI treatment | Circulation | IL-2 and TNF-α secretion; Treg, B cells ; MDSC | IL-2, TNF-α, IL-6 secretion, IL-10 secretion; B cells,Treg, CTLA-4+ cells ; MDSC | |
| Spleen | Mxd4 | Treg, CTLA-4+ cells | ||
| Tumor | Mxd4, cMyc, TGF-b; CTLA-4+ cells; DC myeloid cells ; TAM ; | Agr2 ; B cells; Treg ; TAM | ||
| Pathway alteration upon CDKI treatment | DNA Damage repair | Induced | Unaffected | |
| PI3K-Akt | Downregulated | Unaffected | ||
| Wnt signaling | Activated | Unaffected | ||
| Epigenetic regulation | Downregulated | Induced | ||
| JAK-STAT signaling | Downregulated | Induced | ||
| EMT | Activated (boosted in the combination) | Not induced | ||
TIL - tumor-infiltrating lymphocytes; GIT - gastrointestinal tumor; MDSC - myeloid-derived suppressor cells; TAM - tumor-associated macrophages; CDK - cyclin-dependent kinase; CDKI - cyclin-dependent kinase inhibitor; ICI - immune checkpoint inhibition; DC - dendritic cells; EMT - epithelial-mesenchymal transition.