The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.

Immunotherapy is currently transforming cancer treatment. Notably, immune checkpoint blockers (ICB) have shown unprecedented therapeutic successes in numerous tumor types, including cancers that were traditionally considered as nonimmunogenic. However, a significant proportion of patients do not respond to these therapies. Thus, early selection of the most sensitive patients is key, and the development of predictive companion biomarkers constitutes one of the biggest challenges of ICB development. Recent publications have suggested that the tumor genomic landscape, mutational load, and tumor-specific neoantigens are potential determinants of the response to ICB and can influence patients' outcomes upon immunotherapy. Furthermore, defects in the DNA repair machinery have consistently been associated with improved survival and durable clinical benefit from ICB. Thus, closely reflecting the DNA damage repair capacity of tumor cells and their intrinsic genomic instability, the mutational load and its associated tumor-specific neoantigens appear as key predictive paths to anticipate potential clinical benefits of ICB. In the era of next-generation sequencing, while more and more patients are getting the full molecular portrait of their tumor, it is crucial to optimally exploit sequencing data for the benefit of patients. Therefore, sequencing technologies, analytic tools, and relevant criteria for mutational load and neoantigens prediction should be homogenized and combined in more integrative pipelines to fully optimize the measurement of such parameters, so that these biomarkers can ultimately reach the analytic validity and reproducibility required for a clinical implementation. Clin Cancer Res; 22(17); 4309-21. ©2016 AACR.

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The growth and progression of solid tumors involves dynamic cross-talk between cancer epithelium and the surrounding microenvironment. To date, molecular profiling has largely been restricted to the epithelial component of tumors; therefore, features underpinning the persistent protumorigenic phenotype of the tumor microenvironment are unknown. Using whole-genome bisulfite sequencing, we show for the first time that cancer-associated fibroblasts (CAFs) from localized prostate cancer display remarkably distinct and enduring genome-wide changes in DNA methylation, significantly at enhancers and promoters, compared to nonmalignant prostate fibroblasts (NPFs). Differentially methylated regions associated with changes in gene expression have cancer-related functions and accurately distinguish CAFs from NPFs. Remarkably, a subset of changes is shared with prostate cancer epithelial cells, revealing the new concept of tumor-specific epigenome modifications in the tumor and its microenvironment. The distinct methylome of CAFs provides a novel epigenetic hallmark of the cancer microenvironment and promises new biomarkers to improve interpretation of diagnostic samples.

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Loss of excision repair cross-complementation group 1 (ERCC1), frequently found in lung cancer, and mutations in breast cancer type 1/2 susceptibility genes (BRCA1/2), often found in ovarian, breast and prostate cancers, confer sensitivity to poly-(ADP-ribose) polymerase inhibitors (PARPi). Our work, and that of others, shows that PARPi selectively trigger tumor cell-autonomous immune phenotypes in ERCC1or BRCA-defective contexts. This suggests that PARPi, used in appropriately selected populations, might mediate their therapeutic effects by potentiating anti-tumor immunity.