T cells normalize blood vessels: Tumour vessel normalization and immune checkpoint blockade: a new synergism

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Immune checkpoint inhibitors have emerged as potent immunotherapies for a variety of cancers.1 However, their effectiveness would be enhanced by facilitating T-cell trafficking into solid tumours, which in turn requires functional improvement of the angiogenic vasculature. Abnormal tumour vessels are unable to sustain adequate blood flow, thus potentiating tumour hypoxia and limiting drug and immune cell access. ‘Normalizing’ tumour vessels has emerged as a promising approach to enhance tumour perfusion by increasing vessel organization and coverage of endothelial cells by pericytes.2 However, lack of mechanistic insights and inability to induce durable effects have hampered clinical translation of vessel normalization. While it is unknown whether pre-existing normalized vessels could be a marker for therapeutic efficacy, Tian et al.3 in their recent publication in Nature, demonstrate the prognostic value of a ‘vessel normalization’ signature in cancer. Furthermore, they show a crucial role of interferon gamma (IFNγ)-producing Type 1 T helper (Th1) cells in tumour vessel normalization, which can be further potentiated by immune checkpoint blockade. This is an exciting finding, which links immune checkpoint therapy and vascular normalization, and thus reveals a new synergy with diagnostic and therapeutic implications.
The authors discovered in human breast cancer that a ‘good’ prognosis angiogenic gene cluster, featuring enhanced chemotaxis, smooth muscle cell proliferation and heterotypic cell-cell adhesion, is an indicator for ‘vessel normalization/activation’. In contrast, a hypoxia-related angiogenic gene signature confers poor prognosis. Importantly, the vessel normalization gene cluster correlates with active T-cell receptor (TCR) signalling, suggesting a functional synergy. Using sophisticated mouse models, they further demonstrated that intratumoral T-cell infiltration is dramatically reduced when pericytes are depleted from orthotopically grown breast cancers. This finding reinforces previous studies showing a crucial role of pericytes in tumour vessel integrity, effector cell infiltration and immune rejection. Typically, however, tumour vessel normalization is associated with pericyte maturation/differentiation rather than proliferation as the normalization signature implies.4,5 Novel and significant is the observation that mice lacking activated CD4+ T cells phenocopy the vascular defects of pericyte depletion in the tumour environment. Specifically, orthotopic cancers grown in CD4, TCR or MHC class II knockout mice display an abnormal vasculature with increased vessel leakiness and higher metastatic burden. Importantly, generation of IFNγ+ intratumoral CD4+ effector T cells by combined anti-CTLA-4/PD-1 checkpoint inhibition, even in the absence of CD8+ T cells, improves vessel function and reduces metastases. Data from orthotopic breast tumours, which differ in the degree of CD4+ T-cell infiltration support the notion that low lymphocytic infiltration is associated with leakier vessels, more hypoxia and higher metastatic burden. Similarly, patient-derived xenografts (PDX) from breast, liver, bladder and ovarian cancers when grown in severely immunodeficient mice develop hypoxic features not apparent in the freshly resected tumours. PDX hypoxia and vessel leakiness are alleviated by transfers of T cells skewed towards a Th1 phenotype and subsequent IFNγ enrichment in the tumour microenvironment. Furthermore, computational analysis across several cancer types revealed a positive correlation of CD4+ T-cell infiltration, vessel normalization profile and reduced hypoxia, thus underscoring the prognostic value of these findings.
Of note, Tian et al.3 also show that lack of CD8+ T cells increases metastases without affecting vessel integrity per se, thus demonstrating a specific role for Th1 T cells. While close association of Th1 cells with tumour vessels and IFNγ secretion appears to be crucial for tumour vessel normalization, T-cell influx and reduced neutrophil numbers, how this is orchestrated in the tumour microenvironment is less clear. In the absence of CD4+ T cells, intratumoral endothelial cells increase their pro-angiogenic transcription profile, including VEGF expression.
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