From: CAR T cell-based immunotherapy and radiation therapy: potential, promises and risks
Challenges of CAR T therapy | Advantages of RT combination | Potential drawbacks of combination with RT |
---|---|---|
Limited CAR T cell trafficking | Improved penetration and infiltration. Upregulation of adhesion molecules (ICAM1, VCAM1), chemokines [83]. | High-dose RT causes vascular disfunction and may impair infiltration [103]. |
Hostile metabolic conditions |  | RT-induced cell death mediates release of cellular ‘junk’, purines, ATP, decreases pH [71, 104]. |
Impaired vascularization, hypoxia | Low-dose RT normalizes vascularization, ameliorates hypoxia [71]. | Ablative RT doses may induce endothelial cell death and may aggravate hypoxia. |
Immunosuppressive microenvironment | Induction of immune stimulatory receptors CXCR3 and CCR5 and ligands CXCL-9, CXCL-10, CXCL-16 [87]. | RT promotes infiltration with Tregs, shifts balance towards Tregs, as they are more radioresistant [105]. RT induces chemokine stromal-derived factor 1α (SDF-1α) that attracts infiltration with myeloid-derived suppressor cells [106]. |
T cell exhaustion | Increased expression of MHC class I and II, FAS and FAS ligand, TRAIL [106,107,108]. | RT induces upregulation of immune checkpoint receptors and ligands [105, 109]. |
Tumor heterogeneity | RT can stimulate target antigen expression and mediate cell death on antigen-negative cells via other mechanisms (i.g. TRAIL) [88]. | RT induces tumor mutations, mesenchymal phenotype, invasion, and may contribute to survival of more aggressive clones [110, 111]. |
On-target, off tumor toxicities | RT may improve on-target killing via improved trafficking and boosting target antigen expression [86, 89], 90. | Â |