JITC Editor Picks
David Allard, Bertrand Allard, John Stagg
Journal for ImmunoTherapy of Cancer 2020;8:e000186 (24 February 2020)
Hydrolysis of extracellular ATP into adenosine potently limits immune responses and numerous human cancers maintain immunosuppressive tumor microenvironments, in part, through overexpression of the ATP-hydrolyzing ectoenzyme CD39. In a comprehensive review, David Allard, Bertrand Allard and John Stagg survey the varied mechanisms by which adenosinergic signaling through CD39 impairs both innate and adaptive anti-tumor immune activity, highlighting evidence for potential synergies between targeted blockade of ATP hydrolysis and checkpoint inhibition. A case for therapeutic targeting of CD39 is built based on evidence that the enzyme's activity has been shown to influence key phenotypes for a wide array of immune cells, including (but not limited to) macrophage phagocytosis, neutrophil chemotaxis, T cell exhaustion, Treg function, and myeloid-derived suppressor cell infiltration into the tumor microenvironment. In preclinical models, CD39 inhibition has been shown to impair secondary site growth as well as synergize with checkpoint blockade in models of metastatic lung cancer, and promising anti-tumor effects have been seen with targeted blockade or genetic depletion of CD39 in models of liver cancer, sarcoma and subcutaneous cancers as well. Although sustained inhibition of adenosinergic signaling may lead to toxicities due to altered platelet function, the review makes a compelling case for further investigation of CD39 as a therapeutic target due to its multi-faceted regulatory effects on the tumor-immunity cycle.
Esther Lutgens, Tom T.P. Seijkens
Journal for ImmunoTherapy of Cancer 2020;8:e000300 (6 February 2020)
Immune checkpoint inhibitors have become the standard of care for multiple cancer types, and rapid-onset cardiovascular adverse events such as myocarditis, arrhythmia and cardiomyopathy have been well-documented in patients treated with these agents. Gradually developing cardiovascular diseases, such as atherosclerosis, in the context of checkpoint blockade have received relatively little attention, by contrast, despite robust evidence for the role of immune checkpoint proteins in vessel wall pathogenesis. Drawing on published data in preclinical models that demonstrates modulation of atherosclerotic progression through interventions directed toward PD-1 and CTLA-4, Esther Lutgens and Tom Seijkens' hypothesis makes a case for further study into the effects of checkpoint inhibition on inflammatory plaque formation and progression inside vessel walls. In human trials, myocardial infarctions or strokes have been reported at rates ranging from 1% to 3% in patients receiving checkpoint blockade for lung cancer, indicating that treatment may have aggravated existing plaques. Furthermore, autopsy studies have revealed altered immune cell composition in atherosclerotic lesions from patients treated with checkpoint blockade, specifically a marked bias toward T cell infiltration into vessel plaques. The paper provides rationale for more active risk-management in patients treated with checkpoint blockade, in order to reduce the risk of long-term cardiovascular disease.
Jie Sun, Zicheng Zhang, Siqi Bao, Congcong Yan, Ping Hou, Nan Wu, Jianzhong Su, Liangde Xu, Meng Zhou
Journal for ImmunoTherapy of Cancer 2020;8:e000110 (10 February 2020)
Long non-coding RNAs (lncRNAs) are critical regulatory elements that play important roles in the development and differentiation of several immune cell lineages. Reasoning that lncRNA expression could be used to develop a quantitative molecular signature of tumor-infiltrating immune cells, Jie Sun and colleagues extracted publically available datasets from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) to obtain clinical information and transcriptional profiles for a total of 1533 patients with non-small cell lung cancer. To narrow in on an immune cell specific signature, transcriptional profiles of 115 purified cell lines representing 19 cell types were obtained from GEO and processed and filtered to identify hallmark lncRNAs. Focusing on the 57 lncRNAs that were highly expressed across all 19 immune cell types, differential expression analysis revealed 17 lncRNAs that were upregulated in immune cell lines and downregulated in NSCLC, which were considered as tumor-infiltrating lymphocyte transcripts (TILncRNAs). Using univariate Cox proportional hazard ratio analysis to identify transcripts that associated with patient overall survival time, a prognostic signature was developed based on 7 TILncRNAs. Across three different datasets, with gene expression quantified by multiple platforms, patients stratified as high-risk by the TILncRNA signature had significantly lower 5-year overall survival rates than the low-risk group. Furthermore, the TILncRNA signature had discriminatory power in patients with similar checkpoint gene expression levels. Although further validation is needed, the signature could be a promising biomarker to identify patients who will benefit from checkpoint blockade.
Ssu-Hsueh Tseng, Sung-Taek Park, Brandon Lam, Ya-Chea Tsai, Max A Cheng, Emily Farmer, Deyin Xing Chien-Fu Hung
Journal for ImmunoTherapy of Cancer 2020;8:e000480 (27 February 2020)
Pre-clinical evaluation of immunotherapies is hindered by both the necessity of immunocompromised hosts for xenograft models and the failure to recapitulate important micreoenvironmental aspects of stepwise initiation, progression and spread for tumors derived from syngenic cell lines in immunocompetent hosts. To overcome some of these limitations, Ssu-Hsue Tseng and colleagues developed a clinically relevant, genetically induced model of peritoneal carcinamotosis. After intraperitoneal injection and electroporation of oncogenic plasmids, 100% penetrance was evident at 21 days, which manifested as aggressive growth and spread of tumor nodules across organ surfaces as well as in the ascites. The plasmids carried small hairpin RNAs designed to knock down tumor-suppressor p53 as well as overexpression cassettes for AKT and c-Myc, in addition to a luciferase marker for tracking transfected cells and a sleeping beauty transposon, which allows for cut-and-paste insertion into the genome at TA sites. Importantly, all three genetic changes: loss of function of p53 combined with gain-of-function for AKT and c-Myc were required for carcinogenesis. The tumors displayed histological morphologies similar to those seen in human high-grade serous carcinomas and tumor-infiltrating lymphocytes expressed high levels of PD-1, TIM3 and TIGIT, indicative of an immunosuppressive microenvironment. Interestingly, plasmids bearing c-Myc and AKT together with clinically relevant p53 mutants (as opposed to shRNA knockdown constructs) failed to induce tumors in mice with intact immune systems. This system could be an ideal preclinical model for evaluating oncogenic pathways as well as anti-tumor properties of novel therapies in fully immunocompetent hosts.