Radiotherapy Induced Immunogenic Cell Death

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1		Adrien Procureur	+ 1334 word(s)	1334	2021-02-20 02:50:27	\|
2	format correct	Bruce Ren	-21 word(s)	1313	2021-03-16 03:02:45	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers13040678

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence sug-gests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as im-mune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI.

radiotherapy radioimmunotherapy immunogenic cell death immune checkpoint inhibitors combination therapy cancer treatment

1. Introduction

Cancer is the second leading cause of death worldwide and the first in high-income countries ^[1]. Last decade, the development of immune-checkpoint inhibitors (ICI) has radically changed the clinical practice in multiple tumor types. For instance, Pembrolizumab, a humanized IgG4/kappa anti-PD1, is indicated as frontline therapy for advanced melanoma, for PD-L1 ≥50% advanced non-small cell lung carcinoma and for cisplatin-ineligible patient with advanced urothelial cancer. The Food and Drug Administration (FDA) has approved this ICI both for mismatch repair deficient tumors and for high mutational burden tumors, regardless of histology. However, apart from the above cases, most of the patients treated with ICI monotherapy will not have any benefit ^[2]. One of the reasons is the lack of efficient preexisting immune response.

The immune response must be initiated with a unique type of programmed cell death: the immunogenic cell death (ICD). ICD leads to the release of damage-associated molecular patterns (DAMPs) that is required for dendritic cell maturation and activation. Radiation therapy (RT) is a powerful tool to induce ICD and exhibits many advantages: its safety profile is well known; it could be easily associated with various other therapeutics and RT schedule and sequences could be optimized to improve its immune effects. Rare tumoral regression outside the radiation field had been reported for a long time now ^[3]. That phenomenon, better known as abscopal effect, is related to the induction of systemic CD8⁺-dependent immune response ^[4]^[5]^[6]. Today, the association of RT and ICI is relevant, especially because of the up-regulation of checkpoint proteins after tumor irradiation. On the other hand, like most of the ICD inducers, RT has been developed from the paradigm of maximum tolerated dose, not immune-optimized schedule ^[7]. Yet, it is now clear that greater cytotoxicity is not systematically associated with optimal immunogenicity ^[8]. The optimal regimen, dose per fraction and ICI association remain to be defined and evaluated within large cohorts.

2. The Biology of Radiotherapy-Induced ICD

2.1. ICD in Oncology

ICD is defined as a form of regulated cell death that is sufficient to activate an adaptative immune response in immunocompetent syngeneic hosts ^[9]. How does ICD lead to efficient antitumoral-response? The induction of adaptative immune response depends on three parameters: antigenicity, adjuvanticity and microenvironment.

In physiological condition, apoptosis (and in specific settings necroptosis) are more tolerogenic than immunogenic regulated cell deaths ^[10]. Moreover, they fail to induce immune response in the context of central tolerance. Indeed, their antigens are expressed by thymic epithelium during negative selection of lymphocytes. While cancer cells display tumor-associated antigens (neo-antigens or overexpressed embryonic antigens) that are sufficient to lead to T-cell clonal expansion. Despite the intrinsic antigenicity of tumor cells, the immune response remains conditioned by the recruitment, the maturation, and the activation of antigen-presenting cell (APC).

Adjuvanticity refers to a spatiotemporal coordinated and highly specific release or exposure of danger signals required to fully activate APC. It is mediated by the release of damage-associated molecular patterns (DAMPs) allowed by ICD. ICD is triggered by the endoplasmic reticulum stress and/or reactive oxygen species (ROS)-stress ^[11]. It is characterized by three hallmarks: calreticulin (CALR) exposure on the cell membrane, adenosine triphosphate (ATP) secretion and high-motility group box 1 (HMGB1) release into the extracellular space ^[12]^[13]. HSP70 and HSP90 exposure are also involved in ICD.

Lastly, the tumor microenvironment conditions influence dramatically both the priming and the effector phase of the antitumoral-response ^[14]. An immunosuppressive microenvironment disrupts the initiation of immune response through ICD ^[15].

2.2. Radiotherapy as an ICD Inducer

Antitumoral effects of RT is not restricted to induction of double-strand DNA breaks. Ionized radiation induces ROS-stress that leads to ICD through CARL exposition, ATP and HMGB1 release ^[16]. Ionized radiation promotes a pro-inflammatory environment through the release of chemokines and adhesion molecules leading to APC recruitment ^[17]. Besides, IFN type I secretion through STING-signaling pathway is essential to radiation-induce antitumor response ^[18]. T-cell functions and infiltration are also improved, respectively with enhanced MHC class I expression over tumor cells and with vascular remodeling ^[19]^[20].

Conversely, for a second time, these chemokines recruit myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) that promote the immunosuppressive microenvironment ^[21]^[22]. IFNγ secretion from CD8⁺ T-cell, consecutively to RT fractionation, upregulates PD-L1, leading to T cell and NK exhaustion ^[23]. ROS also polarized tumor-associated macrophages to alternatively activated macrophages (M2) leading to PD-L1 upregulation and immunosuppressive cytokine secretion ^[24]. For most patients with metastatic cancer, focal radiotherapy as a standalone treatment fails to achieve an efficient systemic immune response, mainly because of co-inhibitory receptors upregulation and TGFβ secretion from recruited immunosuppressive cells ^[25]. The abscopal effect remains rare. PD-L1 seems to play a critical role in post-irradiation immunomodulation ^[26]. For example, PD-L1 is associated with radiation resistance in patient derived cell line model from head and neck cancer ^[27]. Accumulating evidence, both pre-clinical and clinical, indicates that ICI association with radiotherapy is promising to overcome the radio-induced immunosuppressive tumoral microenvironment ^[28]^[29].

2.3. Radiotherapy and ICI

Irradiated tumor microenvironment is enriched with several immunosuppressive cells; MDSC expresses PD-L1 and inhibit CD8⁺ T-cell and NK-cell activity; Treg exhibits high levels of CTLA4 and PD-L1 and compromise local immune response ^[22]. ICI restores not only cytotoxic activity of T-cell inside the irradiated-tumoral microenvironment, but it also reinvigorates APC activity and converts the irradiated-tumor in an effective in situ vaccine ^[30]. A systemic activity could be obtained. In pre-clinical models, Ipilimumab (IgG1 anti-CTLA4 antibody) induces Treg depletion and raises TCD8⁺/Treg ratio ^[22]. Anti-PD-1 or anti-PD-L1 restore CD8⁺ T-cell cytotoxicity and indirectly causes MDSC depletion, probably via TNF secretion ^[21]. RT-induced ICD, RT tumoral microenvironment reprogramming, and ICI effects are summarized in Figure 1.

Nevertheless, abscopal effect remains hardly reproducible in clinical practice. Above all because optimal RT schedule, dose rate and fractionation are not clearly defined. Until now, radiotherapy has been developed on the basis of maximum tolerated dose paradigm to obtain the best radiation dose delivery. However, maximum tolerated dose is not adapted to maximize the RT pro-immunogenic properties. A paradigm shift is therefore necessary and new protocols are required.

Figure 1. The biological consequences of RT and the synergism effects of RT-ICI association. (A) RT induce ICD leading to DC maturation and activation. However, DC activation is limited by Treg (red cell) through TGFβ secretion. Despite the MHC-1 upregulation, CD8⁺ T-cells remain inhibited by RT-related PD-L1 upregulation, MDSC infiltration and TGFβ secretion. (B) Anti-CTLA4 antibodies induce Treg depletion by ADCC, and DC activity is increased. On the other hand, CD8⁺ T-cells are still inhibited by PD-1/PD-L1 axis. It is only through the addition of anti-PD-1 or anti-PD-L1 antibodies that an effective immune response can be restored. A virtuous cycle is set up. ATP, adenosine triphosphate; CALR, calreticulin; CTLA4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; HMGB1, high mobility group box 1; MDSC, myeloid-derived suppressor cell; MHC-1, major histocompatibility complex class 1; PD-L1, programmed death-ligand 1; TGFβ, transforming growth factor beta. This figure was created using Servier Medical Art templates (Creative Common Attribution 3.0), https://smart.servier.com (access on 29 December 2020).

Several clinical trials have evaluated the benefits of ICI association with RT. The results highly depend on tumoral subtypes.

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