Table 1.
Targeted gene | Gene function | Knockout strategya | Phenotype | Therapeutic application | References | |
---|---|---|---|---|---|---|
IKKα | Activation of NF-kB | Mutation that prevents IKKα activation | Prolonged tumor onset, decreased metastasis occurrence and delayed mortality | Pharmacologic regulation of either expression of maspin or inactivation of NF-kB | [40] | |
TGFβRII | Initiates the downstream TGFβ signaling cascade | DNTGFβRII expressed in epithelial cells | Appearance of early malignant changes | Administration of TGFβ. However, TGFβ is also an immunosuppressive cytokine. Hence, administration of TGFβ might exert opposing effects | [49] | |
TGFβRII | Initiates the downstream TGFβ signaling cascade | DNTGFβRII expressed in CD8+ and CD4+ T | Reduced tumor growth associated with enhanced tumor antigen-specific T cell responses | This strategy could be used in adoptive immunotherapy to render tumor-specific T cells less susceptible to TGFβ-mediated immunosuppression | [53] | |
TGFβ | Immunoregulatory cytokine | Crossing mice with floxed and null alleles of TGFβ1 (Tgfβ1f/n) with CD4-Cre mice | As above | Inhibition of TGFβ by specific monoclonal antibodies. However, systemic inhibition of TGFβ might favor tumor cell growth | [53] | |
TGFβ | Immunoregulatory cytokine | Crossing Tgfβ1f/n with Foxp3-Cre mice | No effects on tumor growth | As above | [53] | |
Klrk1 | Codifies for NKG2D | Deletion of the exons 1b to 6 of NKG2D | Appearance of more aggressive tumors | Treatment with IFNα and IL-2 may result in in vivo expansion and activation of NK cells | [62] | |
TCRδ | Allows thymic selection of γδ T cells and antigen recognition | B6.129P2 Tcrdtm1Mom/J mice are deficient for γδ T cells | Appearance of more aggressive tumors | Zolendronate and IL-2 activate in vivo γδ T cells | [91] | |
Jα18 | Allows thymic selection of iNKT cells and antigen recognition | B6.129-Tcra-Jtm1tg mice are deficient for iNKT cells | Appearance of more precocious and aggressive tumors | Treatment with αGalCer or αGalCer–modulated DC | [98] | |
IDO | Promotes the catabolism of tryptophan | Deletion of the exons 3–5 of the IDO gene | Delayed appearance of palpable tumor in TRAMP IDO−/− mice | Pharmacological inhibition of IDO by 1-methyl-tryptophan | [151] |
aTRAMP mice were crossed with mice carrying the indicated genetic alteration for several generations to generate TRAMP mice of nearly identical background and carrying the additional genetic alteration