Hypoxia and the phenomenon of immune exclusion

Abstract

Over the last few years, cancer immunotherapy experienced tremendous developments and it is nowadays considered a promising strategy against many types of cancer. However, the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of immunotherapy in solid tumors. Despite several mechanisms proposed during the years to explain the immune excluded phenotype, at present, there is no integrated understanding about the role played by different models of immune exclusion in human cancers. Hypoxia is a hallmark of most solid tumors and, being a multifaceted and complex condition, shapes in a unique way the tumor microenvironment, affecting gene transcription and chromatin remodeling. In this review, we speculate about an upstream role for hypoxia as a common biological determinant of immune exclusion in solid tumors. We also discuss the current state of ex vivo and in vivo imaging of hypoxic determinants in relation to T cell distribution that could mechanisms of immune exclusion and discover functional-morphological tumor features that could support clinical monitoring.

Hypoxia Constructing the Prognostic Model of Colorectal Adenocarcinoma and Related to the Immune Microenvironment

“…This finding may provide a possible explanation for the lower survival rate in COAD patients with higher hypoxia level. Currently, it has been reviewed that hypoxia induces immunosuppressive process by affecting immune cell transport and angiogenesis in the tumor microenvironment, and provides a basis for clinical monitoring (Augustin et al, 2020;Pietrobon and Marincola, 2021). More specifically, potential mechanisms by which HIF-1 signaling in the tumor microenvironment promotes immune escape and leads to poor prognosis include: induction of immunosuppressor and immune checkpoint molecule expression, autophagy, exosome release, and novel immunogenic cell death (Vito et al, 2020;You et al, 2020).…”

NSCLC Biomarkers to Predict Response to Immunotherapy with Checkpoint Inhibitors (ICI): From the Cells to in-Vivo Images

“…These radiotracers have been studied mainly to assess tumor resistance in chemotherapy and radiotherapy setting. However, as recently reported by Pietrobon et al [202], the exclusion of lymphocytes from the tumor nest is a common phenomenon that limits the efficiency of ICI in solid tumors (cold tumors) and one hypothesis is that hypoxia, a hallmark of most solid tumors, may be a common biological determinant of immune exclusion in solid tumors.…”

Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy

“…Another HIF family transcription factor, HIF-2α, is also involved in activating hypoxic responses and is structurally similar to HIF-1α apart from the transactivation domain. This difference confers target gene specificity of HIF-1α and HIF-2α, leading to them having both overlapping and unique target genes [ 51 , 52 , 53 ]. Unlike HIF-1α, which is the main regulator of the glycolytic pathway and expressed mainly during the acute phase of hypoxia response (<24 h), HIF-2α is mostly involved in promoting an undifferentiated phenotype of pluripotent cells and drives the chronic response of hypoxia (>24 h) [ 54 , 55 ].…”

“…Effector T-cell infiltration into the tumour is hindered through the upregulation of VEGF to promote dysregulated angiogenesis, and via the downregulation of integrins (αLβ2) on vascular endothelium by upregulating IL-10 production [ 53 , 126 ]. Consequently, the abnormal, disorganised tumour neovasculature lacks the appropriate proteins for adhesion, attraction and extravasation of T-cells, leading to dysregulated trafficking of T-cells into the tumour bed.…”

“…Furthermore, the enrichment of IL-10, VEGF and prostaglandin E2 under hypoxic conditions induces Fas-ligand expression on the tumour vasculature to promote T-cells apoptosis, ultimately leading to reduced T-cell accumulation within the TME [ 16 ]. Hypoxia via HIF-1 also reshapes the extracellular matrix by increasing collagen deposition and inducing stromal fibrosis, which also impede the accessibility of T-cells [ 53 ].…”