Table 3.

Immunogenic effects of RT or RT and immune checkpoint inhibitor combinations observed in preclinical studies.

	Local	Distant	Impact on Survival	Alterations in Local and/or Distant TME
RT-conv. dose [31,32,46,47]	Only delayed tumor growth	↑DM	↓Survival when compared with ablative doses	↓CD8+ T cell (acute) and ↑MDSCs locally ↑PD-L1 expression by tumor cells at the primary site mediated by CD8+ T cell released IFNγ ↑PD-L1 expression by MDSCs at the primary site.
RT-ablative dose [30,31,32,35,36,37,38,39,48,49]	Durable local control Increased local control with multi-frx regimen	Any distant effects are abrogated by chemotherapy DM significantly decreased when RT is combined with an immunomodulator	↑Survival only in the presence of CD8+ T cells; and when RT is combined with activating immunomodulators	↑TAAs and tumor-specific Ag presentation by MHC I within the local TME ↑T cell priming in draining lymph nodes ↑CD4+ and CD8+ T cell infiltration at the local tumor site Batf3 CD8+ DCs and IFNγ are required for any curative effect from RT ↓MDSC and TAMs, but ↑Tregs ↑dsDNA induced IFN β release mediated by cGAS-STING, leading to cross priming ↓cytosolic dsDNA mediated by Trex1 with single dose irradiation >10–12 Gy ↑PD-L1 expression by tumor cells ↑PD-1 expression by CD8+ T cells at both primary and distant sites
RT + anti-CTLA-4 [44,45]	Most tumor response and CR. Best response with multi-frx RT	Significant ↓ DM only with the combined Rx Best response with multi-frx RT	Significant improvement in survival is only observed with the combined Rx	Distant effect is CD8+ T cell dependent Combined Rx led to ↑ infiltration by CD4+ and CD8+ T cells distantly Combined Rx led to ↑tumor Ag specific CD8+ T cells in lymphoid tissue
RT + anti-PD-(L)1 [46,47,48,49,50]	Best tumor response with further improvement over RT alone	Best distant response with most distant CR	Best survival when compared with either Rx alone Best survival with concurrent Rx	Local and distant effects are CD8+ T cell dependent (infiltrating > residing) ↑tumor Ag specific CD8+ T cells locally with RT alone but increased further locally with distant ↑ only after combined Rx ↑PD-L1 expression by tumor cells and MDSCs at both the primary and distant sites ↓↓↓MDSCs at the primary site mediated by CD8+ T cells ↓Tregs at the primary site

TME: tumor micro-environment; RT: radiotherapy; conv.: conventionally fractionated; DM: distant metastases; TAA: tumor-associated antigens; MDSC: myeloid-derived suppressor cell; Ag: antigen; TAM: tumor-associated macrophage; Treg: regulatory T cells; multi-frx: multi-fraction; Rx: treatment.