Tumour immunology: Reducing silence to improve therapy

inflammatory T cells are more inhibitors of programmed cell death Nature Reviews Immunology AOP, published online 6 November 2015; doi:10 1038/

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Tumour immunology: Reducing silence to improve therapy - Nature

inflammatory T cells are more inhibitors of programmed cell death Nature Reviews Immunology AOP, published online 6 November 2015; doi:10 1038/

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All adaptive immune responses are dependent on the acti- they are recognized by different classes of T cells— helper cells that stimulate antibody production and

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proteins in stem cells, become methylated and completely silenced in cancer17- 19 This led to the proposal of an 'epigenetic stem cell model' of cancer whereby

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TH9 immunity includes eosinophils (rEOS), basophils/mast cells(MCt), IL-9 CD4 T cells, and IgA2 B cells certified by peer review) is the author/funder All rights reserved memory T cells Nature immunology 10(8):857-863, 2009 22

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Tumours with a high number of

inflammatory T cells are more responsive to immunotherapy with inhibitors of programmed cell death protein 1 (PD1) and its ligand PDL1, compared with tumours that have a low number of inflammatory T cells.

Reporting in Nature, Peng at al. show

how epigenetic gene-silencing mech- anisms repress T helper 1 (T H

1)-type

chemokine production in ovarian tumours; treatment with inhibitors of epigenetic modifiers reduced tumour volume, increased infiltration of effector T cells and improved the effi- cacy of PDL1 blockade therapy and

T cell transfusion therapy in mice.

The authors hypothesized that

immune-protective genes could be epigenetically silenced in cancer, which would affect cancer progression and response to immunotherapy.

To test this, they used different inhib-

itors of epigenetic modifiers in mouse models bearing human primary ovarian cancer cells or mouse ovarian cancer cells. Treatment with a single agent had no effect, but treatment with an inhibitor of enhancer of zeste homologue 2 (EZH2) together with an inhibitor of DNA methyl- transferase 1 (DNMT1) led to decreased tumour size, increased numbers of tumour-infiltrating

T cells and augmented expression

of the T H 1- type chemokines CXC-chemokine ligand 9 (CXCL9) and

CXCL10. When this treatment was

combined with anti-PDL1 and T cell transfusion, the effect was enhanced.

Thus, epigenetic reprogramming

increased tumour immunity, blocked cancer progression and improved the efficacy of PDL1 checkpoint blockade therapy and T cell therapy.

In a series of experiments, the

authors showed that trimethylation of histone H3 at lysine 23 by EZH2 and DNA methylation by DNMT1 independently mediated the repression of T H

1-type chemokine production by ovarian tumour cells.

Finally, the authors investigated

the clinical implications of their results. The nuclear levels of EZH2 and DNMT1 were determined by immunohistochemistry staining in human ovarian tissues and compared to patient survival data. The median intensity of staining for EZH2 and DNMT1 was used to divide patients into 'low levels' or 'high levels' of these epigenetic modifiers.

Interestingly, the overall survival

rates were lower and disease-free intervals were shorter in patients with high levels of EZH2 or DNMT1 compared with patients that have low levels of these molecules, and this effect was even more pronounced when the level of both enzymes was high. Furthermore, patients with low levels of the epigenetic modifiers had more tumour-associated CD8

T cells,

which were associated with longer overall survival and disease-free intervals. Thus, epigenetic pathways in tumours seem to silence T H

1-type

chemokine expression, repress T cell homing to tumours and determine why some tumours are T cell 'inflamed' and others are not.

To conclude, this study suggests

that reprogramming of epigenetic pathways that are altered in tumours could be an efficient way to increase responsiveness to immunotherapy.

Elisabeth Kugelberg