Samenvatting
Introduction: Targeted radionuclide therapy (TRT) is a systemic treatment with radioactively labeled cancer-specific probes purposed to selectively hit diseased cells. As radioactive labels α- or β--emitters are used, which release their energy in the proximity of the cancer cells, thereby causing irreparable DNA damage. TRT using camelid single domain antibodies (sdAbs) is studied at the VUB, showing high potential in controlling tumor growth. Because little is known about the role of the immune system in the tumor control achieved by TRT, we studied TRT-mediated immune activation.Materials and methods: C57BL/6 mice were inoculated with B16-melanoma cells expressing human CD20 and ovalbumin. After engraftment, mice received fractionated treatment with non-targeting sdAbs or anti-CD20 sdAbs, labeled with α- (225Actinium) or β-- (177Lutetium) particle emitting radioisotopes. Different readouts were evaluated: (1) tumor volume, measured by caliper, (2) gene expression profiling of the tumor microenvironment (TME), evaluated using RT-qPCR, (3) immune cell composition of the TME, evaluated using flow cytometry, (4) systemic immune responses evaluated by stimulation of CD8+ splenocytes with tumor antigens and (5) presence of immune activating signals in serum.
Results: A reduced tumor progression was observed upon treatment of CD20+ melanoma-bearing mice with 225Actinium or 177Lutetium labeled anti-CD20 sdAbs. Immune activation was not observed in mice treated with 177Lutetium labeled anti-CD20 sdAbs. In contrast, our preliminary data suggest that mice treated with 225Actinium labeled anti-CD20 sdAbs have signs of immune activation. We observed (1) ovalbumin-specific CD8+ splenocytes, (2) a significantly increased expression of PD-1, (3) significantly decreased expression of PD-L1 in the TME and (4) an increase in type I IFN in sera.
Conclusion: To our knowledge, this is the first study showing immune activation in a melanoma model upon TRT with α- but not β--decaying radioisotopes. These preliminary findings should be reproduced and the mechanisms leading to immune activation studied. When immune activation upon α-TRT is confirmed, complementing α-TRT with immunotherapy is warranted to fully capitalize on the effects of TRT.
| Datum prijs | 15 jun. 2019 |
|---|---|
| Originele taal | English |
| Begeleider | Ahmet Krasniqi (Promotor) |