Towards Immunotherapy-Induced Normalization of the Tumor Microenvironment

Abstract

Immunotherapies modulate the function of immune cells to eradicate cancer cells through various mechanisms. These therapies are successful across a spectrum of cancers, but they are curative only in a subset of patients. Indeed, a major obstacle to the success of immunotherapies is the immunosuppressive nature of the tumor microenvironment (TME), comprising the stromal component and immune infiltrate of tumors. Importantly, the TME in most solid cancers is characterized by sparsely perfused blood vessels resulting from so-called pathological angiogenesis. In brief, dysregulated development of new vessels results in leaky tumor blood vessels that inefficiently deliver oxygen and other nutrients. Moreover, the occurrence of dysregulated fibrosis around the lesion, known as pathological desmoplasia, further compresses tumor blood vessels and impairs blood flow. TME normalization is a clinically tested treatment strategy to reverse these tumor blood vessel abnormalities resulting in stimulated antitumor immunity and enhanced immunotherapy efficacy. TME normalization includes vascular normalization to reduce vessel leakiness and reprogramming of cancer-associated fibroblast to decompress vessels. How immunotherapies themselves normalize the TME is poorly understood. In this review, we summarize current concepts and progress in TME normalization. Then, we review observations of immunotherapy-induced TME normalization and discuss the considerations for combining vascular normalizing and immunotherapies. If TME could be more completely normalized, immunotherapies could be more effective in more patients.

The Interplay of Tumor Vessels and Immune Cells Affects Immunotherapy of Glioblastoma

“…The normal structural organization of blood vessels is disrupted in tumors leading to the formation of abnormal vessels which are leaky, collapsed, and disorganized, which contributes to hypoxia, alters tumor metabolism, tumor invasion, immune suppression, and creates specific niches in TME [ 20 , 21 ]. Excessive angiogenesis and fibrosis orchestrate together pathogenic signaling to vascular cells and immune cells [ 22 , 23 , 24 ]. As such, the tumor vessels are immature and leaky, with dissociated endothelial cells (ECs) and pericytes (PCs), abnormal in shape and spatial distribution.…”

“…As such, the tumor vessels are immature and leaky, with dissociated endothelial cells (ECs) and pericytes (PCs), abnormal in shape and spatial distribution. Vessels have abrupted blood flow and are characterized by extravascular accumulation of proteins [ 23 ]. This unfavorable TME is characterized by hypoxia, desmoplasia, low pH (acidic), and increased interstitial pressure, which promotes tumor dissemination and survival [ 4 , 20 ].…”

“…The loss of structural integrity and functional aberrations of tumor vessels induce a collapse of blood vessels under the massive growth and interstitial pressure of the solid mass of the tumor. Furthermore, excessive fibrosis is mediated by cancer-associated fibroblasts (CAFs) that endure forces (by an increase in collagen 1 and hyaluronan production) to compress vessels [ 23 , 30 , 31 , 32 ]. Therefore, the tumor vessels show unusual spatiotemporal differences in perfusion [ 33 ].…”

“…Moreover, fibroblasts generate elevated solid stress and tissue stiffness that compress the blood and lymphatic vessels, elevating the interstitial fluid pressure and reducing blood flow. The events may accelerate the invasiveness of tumor cells [ 20 , 23 , 66 ]. Immunosuppression in the GBM TME is the prime reason for the failure of immunotherapy.…”

“…The anti-VEGF antibody bevacizumab, which blocks the VEGF/VEGFR-dependent survival and growth of vasculature, did not elicit the expected results in cancer patients. Further, preclinical studies demonstrated that vessel pruning leads to increased hypoxia, which supports tumor growth and metastatic dissemination [ 23 ]. The concept of vascular normalization or healing aims at restoring a stable phenotype with more fortified and mature vessels with the appropriate pericyte coverage.…”