Rationale for Combining Radiotherapy and Immune Checkpoint Inhibition for Patients With Hypoxic Tumors

Abstract

In order to compensate for the increased oxygen consumption in growing tumors, tumors need angiogenesis and vasculogenesis to increase the supply. Insufficiency in this process or in the microcirculation leads to hypoxic tumor areas with a significantly reduced pO2, which in turn leads to alterations in the biology of cancer cells as well as in the tumor microenvironment. Cancer cells develop more aggressive phenotypes, stem cell features and are more prone to metastasis formation and migration. In addition, intratumoral hypoxia confers therapy resistance, specifically radioresistance. Reactive oxygen species are crucial in fixing DNA breaks after ionizing radiation. Thus, hypoxic tumor cells show a two- to threefold increase in radioresistance. The microenvironment is enriched with chemokines (e.g., SDF-1) and growth factors (e.g., TGFβ) additionally reducing radiosensitivity. During recent years hypoxia has also been identified as a major factor for immune suppression in the tumor microenvironment. Hypoxic tumors show increased numbers of myeloid derived suppressor cells (MDSCs) as well as regulatory T cells (Tregs) and decreased infiltration and activation of cytotoxic T cells. The combination of radiotherapy with immune checkpoint inhibition is on the rise in the treatment of metastatic cancer patients, but is also tested in multiple curative treatment settings. There is a strong rationale for synergistic effects, such as increased T cell infiltration in irradiated tumors and mitigation of radiation-induced immunosuppressive mechanisms such as PD-L1 upregulation by immune checkpoint inhibition. Given the worse prognosis of patients with hypoxic tumors due to local therapy resistance but also increased rate of distant metastases and the strong immune suppression induced by hypoxia, we hypothesize that the subgroup of patients with hypoxic tumors might be of special interest for combining immune checkpoint inhibition with radiotherapy.

Comparative Mathematical Radiotherapy of Some Dog and Human Cancers

“…More so, factors such as age, sex, type of cancer, location of cancer and biological effective dose should be considered. The most relevant formula is BED = nd [1 + (d)/(α/β)] where BED = biologically equivalent dose; d = dose per fraction; α/β = ratio for tumor (10) and n = number of fractions.…”

“…Small doses of hyperfractionated radiation rays lower tissue toxicity by causing reoxygenation and killing hypotic tumor cells e ciently [9] despite. Immunotherapy may be better for hypotic tumors [10]. All tumor models never re ect the full range of complex tumor and the patients [11].…”

A2AR Antagonism with DZD2269 Augments Antitumor Efficacy of Irradiation in Murine Model

“…Hypoxia is common in solid tumors and is caused by increased O2 consumption and delayed angiogenesis. Hypoxia causes immunosuppression, promoting tumor recurrence and leading to the failure of radiotherapy [23]. The hampered antitumor immunity in hypoxic tumors is mainly mediated by adenosine receptor signalling, especially A2AR [24].…”

hERG K+ Channels Promote Survival of Irradiated Leukemia Cells

“…In addition to cell cycle control, radiogenic hERG1 and K v 3.4 activities apparently are required to blunt mitochondrial hyperpolarization and superoxide anion formation in irradiated K562 cells (see Supplementary Figures 2 and 3). Since mitochondrial Ca 2+ overload may trigger radiogenic mitochondrial superoxide anion formation [for review see (Eckert et al, 2019)] one might speculate that radiogenic hERG1 and K v 3.4 activities interfere with Ca 2+ homeostasis during DNA damage response beyond regulating the Ca 2+ /CaM/CaMKII pathway.…”

“…Mitochondria have been identified to contribute to radiationinduced cell damage by formation of superoxide anion radicals [for review see (Eckert et al, 2019)]. To define a potential role of hERG1 and K v 3.4 channels herein modulation of inner mitochondrial membrane potential (DY m ) and mitochondrial formation of superoxide anion radicals were determined by flow cytometry 24 h after irradiation with 0 or 8 Gy ( Supplementary Figures 2 and 3).…”