Skip to main content

Table 2 Impact of RT on challenges of CAR T cell-based therapy. CAR T cell-based therapy faces complex challenges that can be overcome (second column) or aggravated (third column) by RT-mediated mechanisms

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