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Tumour lymph vessels boost immunotherapy

A high level of expression of the growth-factor protein VEGF-C is associated with tumours that have extensive lymph vessels and poor prognosis. It emerges that such tumours are highly susceptible to immunotherapy.
Christine Moussion is at Genentech, South San Francisco, California 94080, USA.

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Shannon J. Turley is at Genentech, South San Francisco, California 94080, USA.
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Advances in our understanding of tumour immunology have led to immense clinical interest in harnessing immune cells to target cancer1. The immune system’s killer (cytotoxic) T cells can search for and destroy abnormal cells that they encounter while patrolling tissues. However, in the suppressive microenvironment of a tumour, such cells often enter a dysfunctional state. A goal of cancer immunotherapy is to trigger or revitalize the antitumour immune response either through vaccination strategies or by using an approach called checkpoint-blockade therapy that dampens immuno-inhibitory signals, such as those of the PD-1 or CTLA-4 pathways2. Writing in Science Translational Medicine, Fankhauser et al.3 show that an increase in the expression of a protein that promotes tumour growth can also make a tumour more responsive to immunotherapy.

Tumours need a vascular supply to grow. Blood vessels bring nutrients and oxygen to a tumour, whereas lymphatic vessels remove fluid and waste. A tumour and the cells in its surrounding milieu stimulate the development of these two branches of the vascular system by secreting proteins that are members of the vascular endothelial growth factor (VEGF) family4.

The protein VEGF-A promotes the generation of new blood vessels (angiogenesis). Decades of work aimed at impairing tumour growth by blocking angiogenesis has led to the approval of drugs that inhibit signalling by members of the VEGF family, with most approaches4 targeting VEGF-A.

VEGF-C promotes lymphatic-vessel formation (lymphangiogenesis) by signalling through the VEGFR3 receptor5. Lymphatic vessels can promote the process of metastasis — tumour-cell spread beyond the primary tumour growth site — by providing a route for cancer cells to exit a tumour and reach nearby structures termed lymph nodes. This process enables tumour cells to grow in lymph nodes, and to disseminate from there to other locations. Many tumours associated with metastasis, such as melanoma and breast cancer, express high levels of VEGF-C and contain a dense network of lymphatic vessels6. Moreover, an increase in VEGF-C expression in tumours is highly correlated with metastasis to lymph nodes, and with a reduction in survival in individuals with different tumour types, including skin, breast and lung cancers7.

Does an increase in tumour lymphangiogenesis always promote tumour growth? Fankhauser and colleagues addressed this question by analysing the role of VEGF-C-driven lymphangiogenesis in tumour growth. They studied mice that express high levels of VEGF-C and provide a model system for studying cancer. When the researchers treated these animals with VEGF-C-blocking antibodies, they observed a surprising result: although high VEGF-C expression is associated with poor tumour prognosis, VEGF-C inhibition in the context of tumour immunotherapy resulted in increased tumour growth. This suggested that VEGF-C might have another, previously unsuspected role in limiting tumour growth by boosting patient responses to immunotherapy.

The authors investigated the basis of this phenomenon. They found a strong positive correlation between VEGF-C levels and the strength of a tumour-specific cytotoxic T-cell response after immunotherapy in their model mice. They also observed a similar association between high VEGF-C expression and boosted immunotherapy responses (Fig. 1) when analysing data from people who have a metastatic form of skin cancer called melanoma. Together, these results suggest that VEGF-C and the lymphatic system might have unexpected roles in aiding cancer immunotherapy. Perhaps VEGF-C levels could be used as a biomarker to identify patients who are likely to respond to immunotherapy.

Figure 1 | Lymph-vessel formation and tumour response to immunotherapy. Fankhauser et al.3 studied the role of lymphatic vessels — the vasculature that provides a drainage system to remove waste from tissues — in the response of tumours to immunotherapy by using mouse models and analysing clinical data. Tumours that express low levels of the growth-factor protein VEGF-C do not have an extensive network of lymph vessels. However, if VEGF-C expression becomes high in a tumour, a dense network of lymph vessels forms. High VEGF-C levels are associated with poor prognosis. One possible reason for this is that lymph vessels provide a route for tumour-cell migration to other locations in the body. VEGF-C drives the expression of the protein CCL21, and Fankhauser and colleagues observed that the presence of CCL21 was associated with the infiltration of inactive immune cells into the tumour. If these tumours were then treated with immunotherapy to boost the immune response, the immune cells were activated and there was a strong tumour response to immunotherapy.

To understand the biology underlying this phenomenon, the authors investigated how the VEGF-C pathway affects immunotherapy responses. Using genetically engineered mice, they demonstrated that VEGF-C signalling, along with expansion of the lymphatic network at the tumour site, enhances the response to many types of immunotherapy, including cancer vaccines and checkpoint blockade. The authors observed that lymphangiogenic tumours with high VEGF-C expression fostered potent antitumour immune responses, inhibiting primary or metastatic tumour growth.

High VEGF-C expression in the authors’ mouse model drove strong production of the protein CCL21. This protein is not usually expressed by tumours. It is expressed by cells that form the blood vessels and the surrounding material known as the stroma8. These are both associated with the body’s lymphoid-organ sites, in which immune cells are initially activated during an immune response.

CCL21 acts as a type of chemoattractant called a chemokine9, that binds the CCR7 receptor on naive T cells (immune cells that have not yet been activated to mount an immune response) and drives the cells to migrate towards greater concentrations of the chemokine. The migration of naive T cells towards higher concentrations of CCL21 enables the cells to exit the bloodstream and enter lymphoid organs that are rich in CCL21. This is a necessary prelude to their activation and participation in an immune response.

The authors observed that their mice with high VEGF-C expression had a high level of naive T cells present within the tumours, and the number of naive T cells could be reduced if the animals were treated with antibodies that block CCR7 activity. Their analysis suggests that CCL21-enriched tumours might mimic lymphoid organs in a way that attracts naive T cells.

Although not addressed by Fankhauser and colleagues, it is interesting to consider whether VEGF-C signalling in tumours might promote the formation of tertiary lymphoid structures10. These are formed from collections of immune cells clustered in structures that have lymph-node-like characteristics. Unusually high levels of CCL21 expression in tissues can be accompanied by formation of tertiary lymphoid structures that have an organized stromal component and specialized blood vessels named high endothelial venules11. These enable the recruitment of naive T cells from the bloodstream into the tissue and are thought to enhance local immune responses11. Because such structures can develop locally within tissues and bypass the need for the lymph node to activate immune cells, their formation in or near tumours might bolster anti-tumour immune responses and improve responsiveness to immunotherapy.

Therapeutics targeting the VEGF family in combination with immunotherapies might increase the tumour response to treatment by increasing the formation of tertiary lymphoid structures and the recruitment of naive T cells, as indicated in mouse models in which combinations of VEGF-A inhibition and checkpoint blockade were tested12. Fankhauser and colleagues raise the provocative idea that lymphatic vessels and active VEGFR3 signalling driven by VEGF-C might be beneficial for individuals with cancer who are being treated with immunotherapy. If this is the case, successful strategies may need to combine vascular-modulating drugs with cancer immunotherapeutics that preserve lymphangiogenic features.

Nature 552, 340-342 (2017)

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