Low Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
Fernanda G HerreraCatherine RonetMaria Ochoa de OlzaDavid BarrasIsaac CrespoMassimo AndreattaJesus Corria-OsorioAodrenn SpillFabrizio BenedettiRaphael GenoletAngela OrcurtoMartina ImbimboEleonora GhisoniBlanca Navarro RodrigoDominik R BertholdApostolos SarivalasisKhalil ZamanRafael DuranClarisse DromainJohn O PriorNiklaus SchaeferJean BourhisGeorgia DimopoulouZoi TsourtiMarius MessemakerThomas SmithSarah E WarrenPeriklis FoukasSylvie RusakiewiczMikael J PittetStefan ZimmermannChristine SempouxUrania DafniAlexandre HarariLana Elias KandalaftSantiago J CarmonaDenarda Dangaj LanitiMelita IrvingGeorge CoukosPublished in: Cancer discovery (2021)
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand Rae1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide and immune checkpoint blockade to patients with immune desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low-T cell infiltrated tumors.
Keyphrases
- low dose
- induced apoptosis
- dendritic cells
- cell cycle arrest
- clinical trial
- high dose
- early stage
- nk cells
- radiation therapy
- end stage renal disease
- oxidative stress
- regulatory t cells
- cell death
- newly diagnosed
- signaling pathway
- peritoneal dialysis
- gene expression
- squamous cell carcinoma
- machine learning
- drug delivery
- ejection fraction
- genome wide
- prognostic factors
- electronic health record
- data analysis
- replacement therapy