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Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
Genetic separation of GvL and GvH reactivity in new recombinant-inbred tumor-resistant mouse strains
V Schirrmacher1, A Griesbach, M Gehring
1GERMAN CANC RES CTR,TUMORIMMUNOL PROGRAM,DIV CELLULAR IMMUNOL,W-6900 HEIDELBERG,GERMANY. GERMAN CANC RES CTR,CENT ANIM FACIL,W-6900 HEIDELBERG,GERMANY.
Abstract:
From a cross between a tumor-susceptible syngeneic mouse strain (DBA/2) and a tumor resistant MHC congenic strain (B10.D2) new recombinant inbred mouse strains were established over many generations of inbreeding and tumor resistance selection. The resistance selected against one DBA/2 derived malignant tumor (ESb) extended to other DBA/2 malignant tumors (SL 2, MDAY-D2) and was thus of more general significance. Since tumor resistance had an immunological basis and since the two parental strains differed in multiple minor histocompatibility antigens (H) as well as in viral superantigens (vSAGs) we determined specificities of cytotoxic T lymphocyte (CTL) responses in vitro. All CTL responses from tumor resistant strains showed not only antitumor reactivity but also rather strong anti-minor H reactivity. There was no relationship between cytolysis and the DBA/2 type vSAG-7 (Mls(a)) expression. We also tested the capacity of immune cells from 7 resistant lines to transfer graft versus leukemia and graft versus host reactivity to ESb tumor bearing DBA/2 mice. Immune cells from one subline were capable of transfering complete protection without development of chronic GVH over a period of 4 months. The resistant parental line B10.D2 and most of the other sublines also were able to transfer GvL reactivity but this was usually associated later with chronic GVH disease caused mortality. These results demonstrate the potential of this genetic approach to separate GvL from GvH reactivity.
Insights
New mouse strains resistant to tumors were developed. These strains show potential for separating anti-tumor immunity from harmful graft-versus-host disease, offering a new approach to cancer therapy.
Area of Science:
- Immunology
- Genetics
- Oncology
Background:
- Developing new mouse models is crucial for understanding tumor resistance.
- Tumor resistance has an immunological basis involving minor histocompatibility antigens and viral superantigens.
Purpose of the Study:
- To establish and characterize new recombinant inbred mouse strains with enhanced tumor resistance.
- To investigate the immunological specificities underlying tumor resistance and graft-versus-leukemia (GvL) reactivity.
Main Methods:
- Crossbreeding of tumor-susceptible (DBA/2) and tumor-resistant (B10.D2) mouse strains.
- Generations of inbreeding and selection for tumor resistance.
- In vitro cytotoxic T lymphocyte (CTL) assays to determine immune responses.
- Graft-versus-leukemia (GvL) and graft-versus-host (GvH) reactivity transfer experiments.
Main Results:
- Selected mouse strains exhibited resistance to multiple DBA/2-derived tumors.
- CTL responses showed both anti-tumor and anti-minor histocompatibility (H) reactivity.
- One subline effectively transferred GvL reactivity without chronic GvH disease, while others did.
Conclusions:
- This genetic approach successfully generated tumor-resistant mouse strains.
- It demonstrates the potential to separate GvL reactivity from GvH disease.
- These findings offer a promising strategy for developing safer cancer immunotherapies.
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