Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming

Abstract

Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis1,2. Vessel normalization (VN) may resolve this paradox3. VN involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia3. 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 expected4, 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.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…The vascular normalization effect observed in this study was attributed to increased CD4 + type 1 T helper (T H 1) cell accumulation and anticancer activity 105 . However, this evidence was derived using CD4 + T cell-deficient animals or anti-CD4 antibody treatment before breast tumour inoculation; thus, the roles of T reg cells versus those of other populations of CD4 + T cells could not be separated.…”

“…Interestingly, ICB of cytotoxic T lymphocyte protein 4 (CTLA-4) and PD-1 can normalize blood vessels in multiple models of transplanted breast and other tumours 105 . The vascular normalization effect observed in this study was attributed to increased CD4 + type 1 T helper (T H 1) cell accumulation and anticancer activity 105 .…”

Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma

“…In our model anti-PD1 therapy could reduce PD1+ T cells in the tumor microenvironment irrespective of PD-L1 expression, suggesting that direct T-cell activation may account for the efficacy of anti-PD1 therapy, even in tumors without PD-L1 expression. T-cell activation by checkpoint inhibitor therapy may directly improve vascular normalization in tumors and may thus enhance the response to antiangiogenic therapy [35,36]. Combining sorafenib or other antiangiogenic agents with checkpoint inhibitor therapy may increase the influx of CD8+ T cells over Treg cells and attenuate tumor-induced immunosuppression via reversal of tumor angiogenesis [37,38], and an objective response rate of more than 50% has been seen in patients with metastatic renal cell carcinoma [39,40].…”

It’s T Time for Normal Blood Vessels

“…In a recent report in Nature, Tian and colleagues now describe an additional layer of regulation, where not only does a normalized vasculature enable T lymphocyte infiltration (Huang et al, 2013), but T lymphocyte infiltration also reciprocally promotes blood vessel normalization (Tian et al, 2017). In the transcriptomes of patient tumors, the authors noted that angiogenesis-related genes associated with a good prognosis (a ''blood vessel normalization'' signature) were also implicated in the T cell receptor signaling pathway, whereas those associated with a bad prognosis were not.…”