ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment

Abstract

SUMMARY Melanomas accumulate a high burden of mutations that could potentially generate neoantigens, yet somehow suppress the immune response to facilitate continued growth. In this study, we identify a subset of human melanomas that have loss of function mutations in ATR, a kinase that recognizes and repairs UV-induced DNA damage and is required for cellular proliferation. ATR mutant tumors exhibit both the accumulation of multiple mutations and the altered expression of inflammatory genes, resulting in decreased T-cell recruitment and increased recruitment of macrophages known to spur tumor invasion. Taken together, these studies identify a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth.

Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage

“…1A) or expression of ATR-P2445L, a clinically-relevant inactive ATR mutant identified from the Cancer Genome Atlas database with a base substitution in the kinase domain ( Fig. 1, A and B) (44). The specificity of the assay was confirmed by showing lack of nonspecific staining in the negative controls, displayed by the omission of either CPD or SIRT1 antibody alone (Fig.…”

RETRACTED ARTICLE: The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage

“…Similarly, ATR is critical to UV DNA damage signaling 28 and is linked with NER 29 – 34 . Furthermore, ATR provides an anti-mutagenic role in a subset of melanomas 35 . We recently described a molecular pathway linking MC1R signaling with XPA through a protein kinase A (PKA)-mediated phosphorylation event on ATR at S435, which accelerates the repair of UV-induced DNA damage 19 .…”

Cancer-Cell-Intrinsic Mechanisms Shaping the Tumor Immune Landscape

“…It has been reported to influence important parameters of immunotherapy response, such as intratumoral T cell influx and expression of immune checkpoints. Transgenic expression of an ATR LOF mutant in the Tyr::CreERT2; Braf V600E ;Pten F/F model for melanoma diminished T cell influx in the tumor, while increasing B cells and macrophages (Chen et al, 2017). This was associated with an increase in expression of Arginase 1, CD206, and PD-L1 in the tumor, suggesting a more T cell suppressed environment.…”