Figure 1.

Radiation simultaneously induces immune suppression and immune activation in the TME. RT induces dsDNA damage both directly and indirectly by ROS formation. Activation (Right): RT triggers release of the cytokines IL-1β, TNF-α, and IL-6 which promote inflammation and inhibit tumor proliferation while IFN-β promotes DC recruitment. CRT expression by the irradiated tissue binds to CD91 on DCs which promotes phagocytosis. Increased antigen uptake by DCs and activation by HMGB1 binding to TLR4 leads to CTL cross priming in draining lymph nodes. Recognition of cognate antigen by the naïve CTL provides Signal 1 required for CTL maturation. Co-stimulation (signal 2) by CD80/86 on the DC with CD28 on the CTL leads to upregulation of the high-affinity IL-2 receptor, CD25, as well as IL-2 secretion by the CTL which promotes T cell proliferation and survival. Release of the chemokines CXCL9, CXCL10, and CXCL16 recruit activated CTLs to the TME which recognize their cognate antigen via MHC class I molecules on the tumor surface. This in turn initiates cytolysis via release of cytokines (IFN-γ, TNF-α), cytotoxic granules (Granzymes, perforins), and direct cell-cell interactions (Fas-Fas ligand). Suppression (Left): CSF-1 promotes recruitment of TAMs to the TME. Production of IL-10 and TGF-β by the TAM promotes Treg recruitment. Together, release of IDO enhances tryptophan consumption resulting in CTL starvation. PD-L1 expression by tumor, TAMs, and Tregs impairs cytotoxicity of activated CTL and promotes exhaustion. Expression of CD25 by Tregs competes with CTL uptake of IL-2 thus indirectly impairing CTL proliferation and survival. CTLA4 expressed by both Tregs and DCs competes with CD80/CD86 for CD28 co-stimulation (signal 2) thus preventing CTL activation and promoting anergy.