Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.

Neurofibromatosis type 1 (NF1) is one of the most common heritable autosomal dominant disorders. Alternative splicing modulates the function of neurofibromin, the NF1 gene product, by inserting the in-frame exon 23a into the region of NF1 mRNA that encodes the GTPase-activating protein-related domain. This insertion, which is predominantly skipped in neurons, reduces the ability of neurofibromin to regulate Ras by 10-fold. Here, we report that the neuron-specific Hu proteins control the production of the short protein isoform by suppressing inclusion of NF1 exon 23a, while TIA-1/TIAR proteins promote inclusion of this exon. We identify two binding sites for Hu proteins, located upstream and downstream of the regulated exon, and provide biochemical evidence that Hu proteins specifically block exon definition by preventing binding of essential splicing factors. In vitro analyses using nuclear extracts show that at the downstream site, Hu proteins prevent binding of U1 and U6 snRNPs to the 5 splice site, while TIAR increases binding. Hu proteins also decrease U2AF binding at the 3 splice site located upstream of exon 23a. In addition to providing the first mechanistic insight into tissue-specific control of NF1 splicing, these studies establish a novel strategy whereby Hu proteins regulate RNA processing.Neurofibromatosis type I (NF1), which affects 1 in 3,500 individuals (11), is one of the most common dominantly inherited autosomal disorders. Loss-of-function mutations in the NF1 gene cause several abnormalities, including development of benign peripheral and optic nerve tumors (neurofibromas and gliomas) and abnormal distribution of melanocytes (café-aulait spots). NF1 patients also have increased risk of developing malignant tumors of neuronal origin (11, 13). The tumor suppression function of NF1 was linked to a domain in its encoded protein, neurofibromin, which is structurally similar to the Ras GTPase-activating protein (GAP) family (13). In addition to its widely accepted tumor suppression function, NF1 also plays a significant role in brain development. About 30 to 60% of children with NF1 mutations develop learning disabilities, ranging from mild cognitive impairment to attention deficit disorders (15).Exon 23a is an in-frame exon encoding 21 amino acids in the NF1 GAP region. This exon is alternatively included, producing two NF1 isoforms (5). The type I isoform does not contain this exon, while the type II isoform does. The ratio of the two isoforms varies in different tissues and during development. The type I isoform is predominantly expressed in neurons of the adult central nervous system (21, 25) and shows 10-timeshigher activity in down-regulating Ras activity than the type II isoform (5, 48). In the pheochromocytoma cell line PC12, production of the NF1 type 1 isoform can be induced by nerve growth factor treatment (48). These lines of evidence suggest that a balance of the two isoforms is important during neuronal differentiation. Indeed, when exon 23a was deleted from the NF1 locus by gene targ...