Mutual Regulation of Tumour Vessel Normalization and Immunostimulatory Reprogramming

Abstract

Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis ^{1, 2} . Vessel normalization (VN) may resolve this paradox ³ . VN involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia ³ . While these processes alter tumour progression, their regulation is poorly understood. Here we show that Type 1 T helper (Th1) cells play a crucial role in VN. Bioinformatic analyses revealed that gene expression features related to VN correlate with immunostimulatory pathways, especially T lymphocyte (TL) infiltration/activities. To delineate the causal relationship, we employed various mouse models with VN or TL deficiencies. While VN disruption reduced TL infiltration as expected ⁴ , reciprocal depletion or inactivation of CD4 ⁺-TLs decreased VN, indicating a mutually-regulatory loop. Additionally, CD4 ⁺-TL activation by immune checkpoint blockade (ICB) increased VN. IFNγ ⁺ Th1 cells are the major population associated with VN. Patient-derived xenograft (PDX) tumours growing in immunodeficient animal hosts exhibited enhanced hypoxia compared to the original tumours in immunocompetent human hosts, which was reduced by adoptive Th1 transfer. Our findings elucidate an unexpected role of Th1 in vasculature and immune reprogramming. Th1 cells may be a marker and a determinant of both ICB and anti-angiogenesis efficacies.