Background
TAA, tumor, death, cancers
MALIGNANCIES, TUMOR, COLD, CANCERS
ICIs are a key compound in the therapeutic arsenal approved in the metastatic setting for a number of solid malignancies [This lack of efficacy of ICIs has been intensively explored, looking for answers within the tumor microenvironment (TME) and the characterization of tumor-infiltrating lymphocytes (TILs), which brought out the ‘cold’ and ‘hot’ tumor concepts. Considering theses evidences, which testify the central role of the immune context, signatures have been designed and have demonstrated their prognostic values reaching a superior accuracy than the classical AJCC/UICC TNM [Radiotherapy (RT) has been shown to trigger immunogenic cell death with HMGB1 (High Mobility Group Box 1) release by tumor cells and dendritic cells (DCs) activation through TLR4, allowing a tumor antigen-specific T cell immunity [In preclinical models of CT26 and B16 murine cancers, we assessed the effect of several radiotherapy doses per fraction on PD-L1 and TIGIT expression levels. Results suggest that irradiation using a moderate hypofractionation schedule is more likely to trigger PD-L1 and TIGIT expression, justifying our therapeutic approach that targets both receptors. Furthermore, the triple association of anti-TIGIT, anti-PD-L1, and concomitant RT with a 3 fractions of 8 Gy schedule was correlated with better survival in this model compared to all other 3x8 Gy regimens, i.e., anti-PD-L1 plus RT 3x8 Gy, anti-TIGIT plus RT 3x8 Gy, and RT 3x8 Gy alone [Thus, based on the clinical trial association of tiragolumab and atezolizumab and our preclinical data with additional SBRT, we believe that a trial combining these therapies will be important to confirm the safety and efficacy of such an approach. The rationale supporting this study is provided in Fig. 
Rationale: SBRT induces immunogenic cell death, which promotes TAAs and/or TNAs uptake by DCs. Then DCs migrate into the DLN in order to prime naive T cells. After activation in the DLN, CD8 T cells join irradiated and non-irradiated lesions to perform their anti-tumor immune function. CD8 T cell: CD8 T lymphocyte; DC: dendritic cell; DLN: draining lymph node; PD-L1: programmed death-ligand 1; PVR: poliovirus receptor; SBRT: stereotactic body radiation therapy; TAA: tumor-associated antigen; TNA: tumor neoantigen; TIGIT: T cell immunoreceptor with Ig and ITIM domains