The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway
J. Guan et al. Cancer Cell Volume 39, Issue 1, P109-121.E5, January 11, 2021
DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity
C. Lu et al. Cancer Cell Volume 39, Issue 1, P96-108.E6, January 11, 2021
Summary of the findings
The great success of anti-PD-1 therapy against tumors defective in DNA mismatch repair (dMMR) highlights the role of tumor mutational burden (TMB) as a predictive biomarker in onco-immunotherapy. However, primary resistance exists in about 50% of dMMR tumor patients. Consistently, half of dMMR tumors with TMB-High have low level of T-cell infiltration. The mechanism concerning the neoantigen-independent immune profile in dMMR tumors is largely unknown. Given that innate sensing-mediated costimulatory signal is required for T-cell-dependent immune checkpoint blockade, we hypothesize that dMMR may trigger certain DNA sensing to benefit the aforementioned clinical outcome. By screening the DNA sensing pathways correlative to dMMR patients’ prognosis, we found that patients with lower cGAS/STING expression in their tumor tissues were more likely to survive their cancers shorter than those with higher expression. We confirmed this in dMMR mouse models. We show that depleting the cGAS-STING pathway in tumor cells defective in MMR factor MLH1 (dMLH1) badly impairs tumor-infiltration of T cells. Our mechanistical studies reveal that dMLH1, which is seen in about half of dMMR tumors, induces aberrantly hyperactive DNA excision by exonuclease 1 (Exo1), prompting the severely damaged DNA to release to the cytoplasm. This activates the cGAS-STING pathway and stimulates IFN production, leading to T-cell proliferation and tumor infiltration. Radiation further stimulates the immune signaling response. Correspondingly, dMLH1 cancer patients who resist anti-PD-1 therapy express low levels of cGAS/STING. These studies refine our understanding of the mechanisms underlying immunotherapy sensitivity and identify new biomarkers for predicting efficacy in dMMR patients.
Future impact of the findings
The findings in our study suggest that TMB-mediated neo-antigens in dMMR tumors is not enough for effective immunotherapy. The newly identified biomarkers of the factors involved in the cGAS-STING pathway could steer how dMMR tumors are treated in the future. Thus, evaluating the status of tumors’ cGAS-STING pathway factors could decide whether patients will benefit from immunotherapy. Additionally, since radiation stimulates the cGAS-STING immune signaling in dMLH1 tumor cells, delivering radiation before immunotherapy could further enhance the effectiveness of these therapies in dMMR patients.
