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Cancer Immunology Research
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What We're Reading

A Sampling of Highlights from the Literature

Article Recommendations from Our Deputy and Senior Editors

DOI:  Published February 2020
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Improving CAR T-cell therapy for solid tumors


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Perfecting CAR therapy (from Oreca 07-Gibson via motors.all-free-photos.com)

Multiple mechanisms thwart the efficacy of CAR T cells. Lynn et al. overexpress the activating c-Jun AP1 complex in various CAR T cells, yielding resistance to exhaustion and strong antitumor activity in multiple in vivo models. This suggests an approach that may overcome a major hurdle to the efficacy of CAR T cells against solid tumors. Reinhard et al. developed CAR T cells that recognize the solid tumor antigen CLDN6, expressed in adults exclusively on tumors. When combined with lymph-node presentation to T cells of a CLDN6 RNA nanoparticle vaccine, these CAR T cells expanded, produced copious IFNγ, and eradicated tumors in multiple solid tumor models.

Lynn RC, …, Mackall CL. Nature 2019 Dec 4;576:293–300.

Reinhard K, …, Sahin U. Science 2020 Jan 2. DOI: 10.1126/science.aay5967.

Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor immunity


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Inflammasome activity critical for antitumor effects of anti-CD39 (from Aiyaya via Wikimedia Commons)

Excess extracellular ATP in the tumor microenvironment is converted to adenosine in a process started by CD39, promoting immune suppression. A monoclonal antibody that targets the catalytic site of CD39 prevents immunosuppression and decreases tumor growth. T-cell activity is stimulated from intratumoral macrophage pyroptosis and inflammasome activation, with IL18 release fostering a “hot” tumor and ultimately reversing immunosupression.

Li X-Y, …, Smyth MJ. Cancer Discov 2019 Dec;9:1754–73.

An intra-tumoral niche maintains and differentiates stem-like CD8+ T cells


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Intra-arboreal nest niche (from D. Stanley via Flickr)

Effective antitumor responses rely on “nests” of TCF1+ stem-like CD8+ T cells within tumors that continually differentiate into effector T cells, a process entailing transcriptional and epigenetic changes. These niches resemble T-cell regions of lymph nodes and contain antigen-presenting cells. Patients with progressive cancer have fewer nests within their tumors and impaired CD8+ T-cell responses. Thus, the failure to accumulate these lymphoid-like nests may predict immune failure because of the inability to provide an ongoing supply of new effector cells, even if these cells become exhausted in the tumor microenvironment.

Jansen CS, …, Kissick H. Nature 2019 Dec 11;576:465–70.

Targeted deletion of PD-1 in myeloid cells induces antitumor immunity


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Repercussions from emergency myelopoiesis thwarted by PD-1 deletion (from U.S. Army)

We generally think of PD-1 as acting to impede T-cell proliferation and abet exhaustion. However, the “emergency myelopoiesis” instigated by tumor progression generates populations of myeloid-derived suppressor cells that also express PD-1. Deleting PD-1 in mouse myeloid cells skewed development toward “effector” monocytes and DCs, leading to a greater increase in antitumor T-cell responses than deleting PD-1 from T cells. Thus, blockade of PD-1 also works through the myeloid compartment, which may be critical for achieving therapeutic benefit.

Strauss L, …, Boussiotis VA. Sci Immunol 2020 Jan 3;5:eaay1863.

The PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways


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Positive cis-ter interactions (from Bmewett via Pixabay)

PD-L1 and CD80 can form heterodimeric pairs on the surface of antigen-presenting cells (APC). Homodimeric CD80 on APCs can bind CTLA-4 on regulatory T cells and be transcytosed, reducing the stimulatory capacity of APCs. The heterodimers on APCs cannot be transcytosed and do not interfere with stimulatory CD80 binding to T-cell CD28 yet prevent inhibitory binding of PD-L1 to PD-1 on T cells. Anti–PD-L1 treatment licenses CD80 transcytosis, which is thwarted by anti–CTLA-4 blockade, preserving APC CD80 levels. This provides a rationale for combining anti–PD-L1 and anti–CTLA-4 immunotherapies and for use of anti–PD-L1 reagents that do not interfere with CD80:PD-L1 interactions.

Zhao Y, …, Hui E. Immunity 2019 Dec 17;51:1059–73.

GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment


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GCN2 driving immunosuppression (from “Driving wild cattle in the Maremma,” The Penny Magazine, 1832)

GCN2 is a Ser-Thr kinase responsive to changes in nutrient availability. Its deletion in myeloid cells increases antitumor responses and decreases tumor growth, substantially altering the inflammatory signatures in the melanoma transcriptional landscape. Without GCN2, the phenotype of macrophages and myeloid cells becomes proinflammatory. The GCN2-supported suppression requires transcription factor ATF4, and ATF4 siRNA decreases tumor growth. Thus, GCN2 drives immune suppression through myeloid cells and provides a potential target for immunotherapy.

Halaby MJ, …, McGaha TL. Sci Immunol 2019 Dec 13;4:eaax8189.

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Cancer Immunology Research: 8 (2)
February 2020
Volume 8, Issue 2
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A Sampling of Highlights from the Literature
Cancer Immunol Res February 1 2020 (8) (2) 159;

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    • Improving CAR T-cell therapy for solid tumors
    • Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor immunity
    • An intra-tumoral niche maintains and differentiates stem-like CD8+ T cells
    • Targeted deletion of PD-1 in myeloid cells induces antitumor immunity
    • The PD-L1:CD80 cis-heterodimer triggers the co-stimulatory receptor CD28 while repressing the inhibitory PD-1 and CTLA-4 pathways
    • GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment
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