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Abstract
Purpose
We have previously demonstrated in a murine colorectal cancer model that normofractionated RT (normoRT: 18 × 2 Gy) induced MDSC infiltration and PD-L1 expression, while hypofractionated RT (hypoRT: 3 × 8 Gy) induced Treg. Here, we wanted to assess whether the association of normoRT with treatments that target two radiation-induced immunosuppressive pathways (MDSC and PD-L1) could improve tumor control.
Materials and methods
Subcutaneous tumors were induced using colon tumor cells (CT26) in immunocompetent mice (BALB/c) and were treated with RT alone (18 × 2 Gy or 3 × 8 Gy), or concomitantly with 5-Fluorouracil (5FU) (10 mg/kg) to deplete MDSC, and/or anti-PD-L1 (10 mg/kg). We assessed the impact of these combinations on tumor growth and immune cells infiltration by flow cytometry. In addition, we performed tumor rechallenge experiments and IFN-γ ELISpots to study the long-term memory response.
Results
Even though tumor growth was significantly delayed in the RT + 5FU compared to 5FU and untreated groups (p < .05), there was no significant difference between RT + 5FU (CRT) and RT alone. The rate of MDSC increased significantly 1 week after the end of normoRT (8.09% ± 1.03%, p < .05) and decreased with the addition of 5FU (3.39% ± 0.69%, p < .05). PD-L1 expressing tumor cells were increased after treatment. Adding anti-PD-L1 significantly delayed tumor growth, achieved the highest complete response rate, and induced a long-lasting protective specific anti-tumor immunity.
Conclusions
These results tend to demonstrate the interest of inhibiting two radiation-induced immunosuppressive mechanisms. In patients, the combination of normoRT with 5FU is already the standard of care in locally advanced rectal cancer. Adding an anti-PD-L1 to this treatment could show promising results.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
Additional information
Funding
Notes on contributors
Jihane Boustani
Jihane Boustani, PhD is a radiation oncologist and researcher at University Hospital of Besançon, Besançon, France.
Benoit Lecoester
Benoit Lecoester, MD, is a medical student and researcher at University Hospital of Besançon, Besançon, France.
Jérémy Baude
Jérémy Baude, MD, is a medical student and researcher at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Charlène Latour
Charlène Latour, is a project engineer at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Emeric Limagne
Emeric Limagne, PhD, is a professor and researcher at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Riad Ladjohoulou
Riad Ladjohoulou, is a radiobiologist researcher at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Véronique Morgand
Véronique Morgand is a technician at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Lisa Froidurot
Lisa Froidurot, is a technician at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
François Ghiringhelli
François Ghiringhelli, PhD, is a medical oncologist and professor at Center Georges-Francois Leclerc Cancer Center, Dijon, France.
Gilles Truc
Gilles Truc, PhD, is a radiation oncologist and professor at Center Georges-Francois Leclerc Cancer Center, Dijon, France
Olivier Adotévi
Olivier Adotévi, PhD, is a medical oncologist and professor at University Hospital of Besançon, and head of UMR1098 RIGHT, Besançon, France.
Céline Mirjolet
Céline Mirjolet, PhD, is a radiobiologist researcher at Center Georges-Francois Leclerc Cancer Center, Dijon, France.