Hypoxia interaction with immune responses - new role of hypoxia-targeted drugs? - PDF Version

Tumour hypoxia is a well known and extensively studied adverse factor in radiotherapy of cancer. Oxygen is needed for the radiation to be effective, and the radiosensitivity of cells decreases to half the maximum level at an oxygen concentration of about 0.5-1%. This is called the oxygen effect in radiobiology (RB). The effect occurs because the DNA damage that is caused by the radiotherapy to the cancer cells is fixed into a permanent irreparable state when oxygen is present, but can be repaired more easily by the cancerous cell pathways under hypoxia. In addition to this effect, hypoxia promotes invasive growth and formation of metastases, increasing its adverse effect in the clinic. Hypoxia is a common feature of solid tumours, and understanding its biological impact is an essential part of the radiobiology field.

Since the pioneering work that was performed by Thomlinson and Gray in 1955, it has become clear that viable cells exist at the edge of necrotic regions in solid tumours, where the oxygen concentration is lower than that required to kill the cells efficiently by radiation. In the 1980s, the Eppendorf pO2 histograph was launched. This introduced the possibility to measure oxygen levels in patient tumours, which was a breakthrough for clinicians to understand the size of the hypoxia problem. Several strategies have been proposed to combat hypoxia. Improvements in patient outcome have been demonstrated when radiotherapy is combined with carbogen and nicotinamide therapy to increase oxygen delivery, or when radiotherapy is combined with nimorazole to radiosensitise hypoxic cells. Much attention has also been paid to hypoxia-activated prodrugs. These drugs are activated in cells by an enzymatic reduction reaction, which is inhibited by oxygen. Candidates such as evofosfamide (also known as TH-302) and tarloxotinib bromide (TH-4000) are currently under test in clinical trials. Among many other approaches, addition of the antidiabetic drug metformin has been proposed as an inexpensive and well-tolerated way to reduce hypoxia and radiosensitise tumours.

The introduction of immunotherapy into the radiation research field has led to the identification of a new and exciting role of hypoxia, namely in evasion of immune system cells. Emerging data indicate that hypoxia promotes a tumour cell's ability to avoid attachment by immune cells. Moreover, it is possible that hypoxic regions within the tumour are resistant to immunotherapy as well as radiotherapy. It has even been argued that hypoxia could be a reason why immunotherapy often shows limited success. Different mechanisms have been proposed for the development of this resistance, and this is now a research area of great interest. In addition, novel data suggest that hypoxia-targeted drugs may not only enhance the killing of hypoxic cells directly, but may also increase the local immune responses towards tumour cells. By targeting the interaction between hypoxia and immune responses, a new role for the drugs in combination therapies with radiation or immune checkpoint blockage has been suggested. Investigations of this role in combination with radiotherapy are still limited. However, results that address this role in combination with immunotherapy are emerging and promising.

In this issue of the RB corner, we share a couple of recently published papers that exemplify research on the topic. In preclinical work, mechanisms that underlie the interaction between hypoxia and tumour immune responses have been addressed by Murthy et al. (2019). Moreover, the benefit of hypoxia-targeted drugs in combination with immune checkpoint blockage has been investigated by Jayaprakash et al. (2018) through use of TH-302, and by Scharping et al. (2017), who have used metformin. In clinical work, the effect of metformin on immune responses in oesophageal cancer has been studied by Wang et al. (2020), and the search for a combined immune and hypoxia biomarker of chemoradiotherapy outcome in head and neck cancer has been reported by Nicolay et al. (2020).

Literature

Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer. 1955; 9:539–49.

Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene 2017, 36:439-445.

Abou Khouzam R, Goutham HV, Zaarour RF, Chamseddine AN, Francis A, Buart S, Terry S, Chouaib S. Integrating tumor hypoxic stress in novel and more adaptable strategies for cancer immunotherapy Semin Cancer Biol. 2020; 65:140-154.

Intratumoural Hypoxia Reduces IFN-γ–Mediated Immunity and MHC Class I Induction in a Preclinical Tumour Model

Targeted Hypoxia Reduction Restores T cell Infiltration and Sensitises Prostate Cancer to Immunotherapy

Efficacy of PD-1 Blockade is Potentiated by Metformin-Induced Reduction of Tumour Hypoxia

Low-Dose Metformin Reprogrammes the Tumour Immune Microenvironment in Human Oesophageal Cancer: Results of a Phase II Clinical Trial

Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer – Results from a Prospective Imaging Trial  

Christina Sæten Fjeldbo & Heidi Lyng
Department of Radiation Biology
Oslo University Hospital
Norway

Christina Sæten Fjeldbo

Heidi Lyng