がん免疫療法の新しい知見

タイトル: Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

概要: BackgroundTransforming growth factor beta (TGF{beta}) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGF{beta} signaling impairs DNA repair competency, which is described by a transcriptomic score, {beta}Alt. Cancers with high {beta}Alt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate the association of {beta}Alt with response to immune checkpoint blockade (ICB). We predicted that high {beta}Alt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB. MethodsWe analyzed public transcriptomic data from clinical trials and preclinical models using transcriptomic signatures of TGF{beta} targets, DNA repair genes, tumor educated immune cells and interferon. A high {beta}Alt, immune poor mammary tumor derived transplant model resistant to programmed death ligand 1 (PD-L1) antibodies was studied using multispectral flow cytometry to interrogate the immune system. ResultsMetastatic bladder patients in IMvigor 210 who responded to ICB had significantly increased {beta}Alt scores and experienced significantly longer overall survival compared to those with low {beta}Alt scores (hazard ratio 0.62, P=0.011). Unexpectedly, 75% of high {beta}Alt cancers were immune poor as defined by low expression of tumor educated immune cell and interferon signatures. The association of high {beta}Alt with immune poor cancer was also evident in TCGA and preclinical cancer models. We used a high {beta}Alt, immune poor cancer to test therapeutic strategies to overcome its inherent anti-PD-L1 resistance. Combination treatment with radiation and TGF{beta} inhibition were necessary for lymphocytic infiltration and activated NK cells were required for ICB response. Bioinformatic analysis identified high {beta}Alt, immune poor B16 and CT26 preclinical models and paired biopsies of cancer patients that also demonstrated NK cell activation upon response to ICB. ConclusionsOur studies support {beta}Alt as a biomarker that predicts response to ICB albeit in immune poor cancers, which has implications for the development of therapeutic strategies to increase the number of cancer patients who will benefit from immunotherapy. Translational RelevanceImmunoncology drugs disrupt the balance established between a patients cancer and immune system. The precise cellular and molecular pathways that lead some patients to respond while others do not remain largely undefined because the biology of the immune microenvironment is incompletely understood. Here we show that loss of immunosuppressive TGF{beta} signaling resulting in immunogenic error-prone DNA repair, reported as a high {beta}Alt score, is strongly correlated with a lack of lymphocytes and interferon signaling, rendering them immunologically "cold." Despite this, high {beta}Alt predict response to immune checkpoint therapy and conversion from immune poor to immune rich in part via NK cell activation. Hence, the {beta}Alt signature identifies a previously unrecognized subset of immune-poor patients who respond to ICB therapy and reveals a therapeutic strategy to increase the number of cancer patients who may benefit.