Person:

Seruggia, Davide

The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, plays a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements. In cancer cells the disruption of CTCF binding at specific loci through somatic mutation or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ cell-specific paralog of CTCF, BORIS (Brother of the Regulator of Imprinted Sites), is overexpressed in multiple cancers, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes novel chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma cells rendered resistant to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of new super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS – to engender regulatory chromatin interactions that support specific cancer phenotypes.

Solid tumors are infiltrated by effector T cells (Teff) with the potential to control or reject them, as well as by regulatory T cells (Treg) that restrict the function of Teff and thereby promote tumor growth.1 The anti-tumor activity of Teff can be therapeutically unleashed and is now being exploited for the treatment of some forms of human cancer. However, weak tumor-associated inflammatory responses and the immune-suppressive function of Treg remain major hurdles to broader effectiveness of tumor immunotherapy.2 Here we show that upon disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, the majority of tumor-infiltrating Treg produce IFN-, followed by stunted tumor growth. Remarkably, genetic deletion of both or even just one allele of CARMA1 in only a fraction of Treg, which avoided systemic autoimmunity, was sufficient to produce this anti-tumor effect, showing that not mere loss of suppressive function, but gain of effector activity by Treg initiates tumor control. Treg-production of IFN- was accompanied by macrophage activation and up-regulation of MHC-I on tumor cells. However, tumor cells also up-regulated expression of PD-L1, indicating activation of adaptive immune resistance.3 Consequently, PD-1 blockade concomitant with CARMA1-deletion caused rejection of tumors that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFN--secretion in the preferentially self-reactive Treg pool does not cause systemic autoimmunity but is sufficient to prime the tumor environment for successful immune checkpoint therapy.