Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma

Abstract

The implementation of novel cancer immunotherapies in the form of immune checkpoint blockers represents a major advancement in the treatment of cancer, and has renewed enthusiasm for identifying new ways to induce antitumor immune responses in patients. Despite the proven efficacy of neutralizing antibodies that target immune checkpoints in some refractory cancers, many patients do not experience therapeutic benefit, possibly owing to a lack of antitumor immune recognition, or to the presence of dominant immunosuppressive mechanisms in the tumor microenvironment (TME). Recent developments in this field have revealed that local radiotherapy (RT) can transform tumors into in situ vaccines, and may help to overcome some of the barriers to tumor-specific immune rejection. RT has the potential to ignite tumor immune recognition by generating immunogenic signals and releasing neoantigens, but the multiple immunosuppressive forces in the TME continue to represent important barriers to successful tumor rejection. In this article, we review the radiation-induced changes in the stromal compartments of tumors that could have an impact on tumor immune attack. Since different RT regimens are known to mediate strikingly different effects on the multifarious elements of the tumor stroma, special emphasis is given to different RT schedules, and the time after treatment at which the effects are measured. A better understanding of TME remodeling following specific RT regimens and the window of opportunity offered by RT will enable optimization of the design of novel treatment combinations.

Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

“…CAFs, as other fibroblasts, possess spindle-shaped morphology (Figure 1), although gained increased proliferation rates [1]. CAFs are extensively described in literature, including [1,[7][8][9][10][12][13][14][15][16][17]. In particular, CAFs can be defined as a heterogenous population of connective tissue cells that contribute to cancer progression by secreting specific molecules, including growth factors, proteases, chemokines and cytokines.…”

“…In particular, CAFs can be defined as a heterogenous population of connective tissue cells that contribute to cancer progression by secreting specific molecules, including growth factors, proteases, chemokines and cytokines. These CAF-secreted factors influence adjacent tumor cells, usually inducing tumor growth, as well as attract immune and inflammatory cells [1,10,18]. Due to the different origin and location, multiple cellular markers may assist identifying CAFs, including vimentin, fibroblast-specific protein 1 (FSP1), desmin, discoidin domain-containing receptor 2 (DDR2), αSMA, PDGF receptor-α (PDGFRα), PDGFRβ, FAP, caveolin 1 (CAV1); and secrete vascular endothelial growth factor (VEGF), as well as immunomodulatory molecules, including IL-10, TGFβ, TNF, IFNγ and IL-6 [1].…”

Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation

“…Radiotherapy is associated with increased radio-resistance of tumors, including NSCLC, likely due to the pro-tumorigenic activity of CAFs [6]. Pro-tumorigenic nature of irradiated CAFs is explained either by direct stimulation of tumor cell viability, or by inhibiting immune cells, such as macrophages, dendritic cells, T cells and natural killers [7][8][9][10][11]. Moreover, one can propose distinct mechanisms of tumor recovery following the therapy and role of CAFs in this scenario.…”

“…Third, radiotherapy itself damages cells surrounding tumor and some of these cells contribute to de novo tumor growth. In any of these scenarios, the role of CAFs can be significant given their immunosuppressive and tumor-supportive functions [8,10], and needs to be further examined.…”

Immune-escape-Mechanismen und Resistenzen gegenüber Immuntherapien

“…Interventionen wie Chemothe-rapie und Bestrahlung fördern die Freisetzung von Tumorantigenen, die dann von APC aufgenommen, prozessiert und T-Zellen präsentiert werden, was zu deren Aktivierung führt. Somit können dominante, immunsuppressive Signalwege zumindest partiell überkommen und dadurch ihre Immunogenität verbessert werden[9].Deshalb stellen Kombinationen von Immuntherapien mit anderen nicht immunogenen Strategien neue Möglichkeiten zur Verstärkung der Immunaktivität dar, was mit einer erhöhten Effizienz der Therapie und einem besseren klinischen Ansprechen von Patienten einhergeht. In der Tat werden derzeit verschiedene Kombinationen in Experimentalmodellen sowie klinischen Studien überprüft.Induktion einer effizienten T-ZellantwortKomponenten des adaptiven Immunsystems sind für die Induktion einer anti-tumoralen Immunantwort verantwortlich und kontrollieren das Tumorwachstum und die neoplastische Transformation.…”