JITC Editor Picks
Jahangir Ahmed, Louisa S Chard, Ming Yuan, Jiwei Wang, Anwen Howells, Yuenan Li, Haoze Li, Zhongxian Zhang, Shuangshuang Lu, Dongling Gao, Pengju Wang, Yongchao Chu, Chadwan Al Yaghchi, Joel Schwartz, Ghassan Alusi, Nicholas Lemoine, Yaohe Wang
Journal for ImmunoTherapy of Cancer 2020;8:e000415 (26 March 2020)
Oncolytic viruses may be a promising option to reduce recurrence and metastasis of solid tumors after surgery due to microscopic deposits of minimal residual disease (MRD) beyond the clearance margins. Reasoning that deletion of the N1L gene (which produces a product that potently suppresses proinflammatory NF-kappa-B signaling) from vaccinia virus may serve to locally enhance the innate antiviral immune responses, Jahangir Ahmed et al. engineered VVdeltaTKdeltaN1L—a replication competent oncolytic virus that controlled a variety of aggressive tumors including lung, pancreatic and head and neck cancers in mouse models. Intratumoral injection of the virus increased the numbers of infiltrating CD8+ and CD4+ T cells, and splenocytes isolated 7 and 14 days after treatment displayed enhanced effector CD8+ T cell populations. Treatment was also associated with elevated levels of proinflammatory cytokines, including IL-1beta and interferon gamma. The addition of IL-12 to the engineered virus further enhanced its antitumor properties, leading to a 90% cure rate, compared to 60% with the parent strain. When given as adjuvant prior to surgical excision of flank tumors, the IL-12-augmented oncolytic virus controlled lung metastases and extended long-term survival. The IL-12-producing oncolytic virus could be a promising agent for use as an adjuvant to surgical treatment of solid tumors.
Nicholas Bevins, Shulei Sun, Zied Gaieb, John A Thorson and Sarah S Murray
Journal for ImmunoTherapy of Cancer 2020;8:e000613 (26 March 2020)
Tumor mutational burden (TMB) values can predict responses to immune checkpoint inhibitor therapy, but calculation methods including the content of gene panels sequenced (the denominator of TMB) and the inclusion of synonymous variants (the numerator of TMB) are not standardized between institutions. To understand the impact of altering these parameters, Nicholas Bevins et al. used publicly available data for more than 9000 tumors from The Cancer Genome Atlas (TCGA) to perform in silico simulations of TMB calculations by six commonly used molecular profiling products. The correlation between panel-based and whole-exome sequencing-based method was linear and the correlations between individual panel-based TMB calculations showed slopes of 0.9-1.1, indicating that the absolute value is comparable between panels. For TMB calculations derived from whole-exome sequencing, inclusion of synonymous variants led to differences of roughly 5-10 variants/Mb specifically in the approximate clinical decision range of TMB <20. By contrast, inclusion of synonymous variants in panel-based TMB calculations did not cause any differences in values for panels of similar size. Although most of the datasets in TCGA were deposited before the widespread use and FDA approval of checkpoint inhibitors, analysis of pan-tumor data showed an inverse correlation between TMB and overall survival, though this relationship varied for individual subgroups of cancers. The analysis provides reassuring confirmation that TMB calculations between the gene panels examined are analytically and prognostically equivalent.
Lucas A Horn, Jeffrey Riskin, Heidi A Hempel, Kristen Fousek, Hanne Lind, Duane H Hamilton, Kristen K McCampbell, Dean Y Maeda, John A Zebala, Zhen Su, Jeffrey Schlom and Claudia Palena
Journal for ImmunoTherapy of Cancer 2020;8:e000326 (17 March 2020)
Tumor cell plasticity induced in the context of an epithelial-mesenchymal transition (EMT) has been implicated in primary resistance to checkpoint blockade. Lucas A. Horn and colleagues demonstrated synergistic tumor control in mouse models of lung and breast cancer through a combination of checkpoint inhibition and EMT modulation. Treatment with a combination of bintrafusp alfa (a bifunctional anti-PD-L1/TGF-B receptor trap) and SX-682 (a clinical stage, small molecule inhibitor that allosterically binds to the intracellular domain of CXCR1/2 and irreversibly inhibits downstream IL-8 signaling) reduced plasticity as measured by expression of mesenchymal fibronectin and vimentin. Single-agent SX-682 or bintrafusp alfa each similarly downregulated expression of matrix metalloproteinases as well as interleukin 1 alpha, and combination treatment caused pronounced modulation of numerous genes involved in remodeling the tumor microenvironment including interferon gamma, CD40lg, Icosl and IL2rg. Serum cytokines from combination-treated mice were marked by high levels of Th1 polarizing cytokines IL-12 and tumor necrosis factor alpha and Th2 polarizing cytokines IL-4 and IL-5. The results highlight the potential benefit of combined blockade of IL-8 and TGF-beta signaling to enhance responses to checkpoint blockade by modulating tumor plasticity.
Lorenzo Galluzzi, Ilio Vitale, Sarah Warren, Sandy Adjemian, Patrizia Agostinis, Aitziber Buqué Martinez, Timothy A Chan, George Coukos, Sandra Demaria, Eric Deutsch, Dobrin Draganov, Richard L Edelson, Silvia C Formenti, Jitka Fucikova, Lucia Gabriele, Udo S Gaipl, Sofia R Gameiro, Abhishek D Garg, Encouse Golden, Jian Han, Kevin J Harrington, Akseli Hemminki, James W Hodge, Dewan Md Sakib Hossain, Tim Illidge, Michael Karin, Howard L Kaufman, Oliver Kepp, Guido Kroemer, Juan Jose Lasarte, Sherene Loi, Michael T Lotze, Gwenola Manic, Taha Merghoub, Alan A Melcher, Karen L Mossman, Felipe Prosper, Øystein Rekdal, Maria Rescigno, Chiara Riganti, Antonella Sistigu, Mark J Smyth, Radek Spisek, John Stagg, Bryan E Strauss, Daolin Tang, Kazuki Tatsuno, Stefaan W van Gool, Peter Vandenabeele, Takahiro Yamazaki, Dmitriy Zamarin, Laurence Zitvogel, Alessandra Cesano and Francesco M Marincola
Journal for ImmunoTherapy of Cancer 2020;8:e000337 (9 March 2020)
Many therapies commonly used in the management of cancer patients induce a functionally unique form of stress-driven regulated cell death that culminates with the activation of cytotoxic T lymphocyte-driven adaptive immunity coupled with the establishment of long-term immunological memory. In a comprehensive review, Lorenzo Galluzzi and colleagues provide an operational definition of this immunogenic cell death, explain the underlying biological mechanisms and describe available assays along with guidelines for interpretation. The Nomenclature Committee on Cell Death recently defined immunogenic cell death as 'a form of regulated cell death that is sufficient to activate an adaptive immune response in immunocompetent syngeneic hosts.' Inducers of immunogenic cell death generally operate by driving emission of danger-associated molecular patterns (DAMPs) such as endogenous RNA, cytosolic DNA, or surface expression of endoplasmic reticulum chaperones. Conversely, the tumor microenvironment may antagonize responses to immunogenic cell death through the presence of regulatory T cells, M2-polarized tumor-associated macrophages and myeloid-derived suppressor cells. In the oncology setting, commonly used methods to assess immunogenic cell death in vitro typically measure cytokine and/or DAMP release or responses of antigen-presenting cells after exposure to dying cells. In vivo assays frequently rely on vaccination or evaluation of an abscopal response. Although interpretation of currently used assays can be challenging, especially given key differences between murine and human immunology, harnessing immunogenic cell death could potentially boost the clinical efficacy of many anti-cancer agents.
Yong Li, Yingqiu Song, Pindong Li, Mingxing Li, Haizhou Wang, Tao Xu, Xiongjie Yu, Yuandong Yu, YunYan Tai, Ping Chen, Xiaojun Cai, Xianhe Wang, Longchao Xiang, Rui Deng, Xiufang Zhang, Liping Gao, Xuanbin Wang, Jing Liuand and Fengjun Cao
Journal for ImmunoTherapy of Cancer 2020;8:e000111 (8 March 2020)Research
Interferon alpha (IFN-a) has been widely and effectively used for the treatment of a variety of cancers, but resistance frequently develops. To study the role of tumor heterogeneity in interferon resistance, Yong Li et al. made use of a three-dimensional fibrin culture system to select and characterize a functionally defined subset of tumor-regenerating cells (TRCs) from previously-treated melanomas. Compared to flask-cultured cells of the same origin, TRCs underwent less apoptosis in response to IFN-a and displayed less activation of STAT1 as well as decreased expression of the apoptosis-related genes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), promyelocytic leukemia (PML) and 2'5'A oligoadenylate synthetase 1 (OAS1). Data from the cancer genome atlas revealed a correlation between high RIG-I expression and improved survival in melanoma patients and overexpression of RIG-I in TRCs restored interferon sensitivity, rescued TRAIL, PML and OAS1 expression in response to treatment and enhanced apoptotic cell death. STAT3 was highly phosphorylated in TRCs, which corresponded with decreased RIG-expression. No differences in IL-6 expression were observed between bulk-cultured cells and TRCs, however, inhibitors of cSRC and integrin beta 3 (ITGB3) both synergized with interferon. In mouse models, combination treatment with IFN-a and ITGB3 inhibitor increased apoptosis rates in ITGB3-high tumor cells. The study provides rationale for combining STAT3 inhibitors with IFN-a to enhance the efficacy of melanoma treatment.