bims-imseme 2020-12-27 papers

Issue of 2020‒12‒27
two papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Hum Immunol. 2020 Dec 16. pii: S0198-8859(20)30436-5. [Epub ahead of print]

PD-1 silencing improves anti-tumor activities of human mesothelin-targeted CAR T cells.

Guodi Liu, Qian Zhang, Dehua Li, Linsong Zhang, Zhangjie Gu, Jibin Liu, Guoping Liu, Mu Yang, Jinwei Gu, Xingbing Cui, Yingjiao Pan, Xiaoli Tian.

Chimeric antigen receptor T (CAR T) cell therapy is a new pillar in cancer therapeutics, and has been successfully used for the treatment of cancers, including acute lymphoblastic leukemia and solid cancers. Following immune attack, many tumors upregulate inhibitory ligands which bind to inhibitory receptors on T cells. For example, the interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands (widely known as PD-L1) on a target tumor limits the efficacy of CAR T cells therapy against poorly responding tumors. Here, we use mesothelin (MSLN)-expressing human ovarian cancer cells (SKOV3) and human colon cancer cells (HCT116) to investigate whether PD-1-mediated T cell exhaustion affects the anti-tumor activity of MSLN-targeted CAR T cells. We utilized cell-intrinsic PD-1-targeting shRNA overexpression strategy, resulting in a significant PD-1 silencing in CAR T cells. The reduction of PD-1 expression on T cell surface strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. This study indicates the enhanced anti-tumor efficacy of PD-1-silencing MSLN-targeted CAR T cells against several cancers and suggests the potential of other specific gene silencing on the immune checkpoints to enhance the CAR T cell therapies against human tumors.

Keywords: Chimeric antigen receptor T; Immunotherapy; Mesothelin; Programmed cell death protein 1; Short hairpin RNA

DOI: https://doi.org/10.1016/j.humimm.2020.12.002

Front Immunol. 2020 ;11 566781

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes.

Niccolò Bianchi, Stefan Emming, Chiara Zecca, Silvia Monticelli.

IFN-β treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-β and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-β, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-β, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-β and provide the bases for further mechanistic insights into these commonly used treatments.

Keywords: IFN-β; gene expression; human T lymphocytes; microRNAs; plasticity; vitamin D

DOI: https://doi.org/10.3389/fimmu.2020.566781