Type 1 T Helper Cells Promote Tumor Vessel Normalization

Angiogenesis inhibitors have mixed effects, both suppressing tumor growth and enhancing metastasis. Vessel normalization can mitigate these negative effects and is associated with increased pericyte coverage, enhanced tumor vessel perfusion, and decreased vascular permeability. However, the processes regulating tumor blood vessel normalization are not well understood. Tian and colleagues found that type 1 T helper cells (T_H1) promote tumor vessel normalization. Analysis of gene expression data from patients with breast cancer revealed a subset of angiogenesis genes associated with poor survival, largely genes related to extracellular matrix disassembly and hypoxia, and a subset of angiogenesis genes associated with a good prognosis, largely genes related to heterotypic cell–cell adhesion and smooth muscle cell proliferation, which are processes controlled by mechanisms that hinder vessel normalization. The good prognosis angiogenesis-associated genes were associated with immune response pathways including T-cell receptor signaling, and vessel normalization promoted the infiltration of T lymphocytes in vivo. Depleting CD4⁺ T cells reduced the ratio of pericytes to tumor endothelial cells, and tumors exhibited increase vessel permeability, suggesting a pericyte deficiency. Further, CD4⁺ T-cell depletion reduced vessel normalization in multiple additional mouse models, but did not affect the vasculature of mice without tumors (except in wounded tissue). Specifically, the subset of IFNγ⁺ T_H1 CD4⁺ T cells were responsible for increasing pericyte coverage and tumor vessel normalization. Immune checkpoint blockade reduced orthotopic breast tumor growth, suppressed pulmonary metastasis, and increased pericyte coverage, the number of CD4⁺ T cells, especially T_H1 cells, and T_H1-mediated vessel normalization. Further, in 7 of 9 PDX models, the transfer of tumors to immunocompromised mice promoted hypoxia, which could be alleviated by T_H1 cell transfer. In addition to describing a role for T_H1 cells in promoting vessel normalization, these findings suggest that improving vessel normalization may potentiate checkpoint blockade by increasing immune cell infiltration.

Tian L, Goldstein A, Wang H, Ching Lo H, Sun Kim I, Welte T, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 2017;544:250–4.

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