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Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses - Pre-Clinical Evidence and Ongoing Clinical Applications.

ABSTRACT: Radiotherapy (RT) primarily aims to locally destroy the tumor via the induction of DNA damage in the tumor cells. However, the so-called abscopal, namely systemic and immune-mediated, effects of RT move over more and more in the focus of scientists and clinicians since combinations of local irradiation with immune therapy have been demonstrated to induce anti-tumor immunity. We here summarize changes of the phenotype and microenvironment of tumor cells after exposure to irradiation, chemotherapeutic agents, and immune modulating agents rendering the tumor more immunogenic. The impact of therapy-modified tumor cells and damage-associated molecular patterns on local and systemic control of the primary tumor, recurrent tumors, and metastases will be outlined. Finally, clinical studies affirming the bench-side findings of interactions and synergies of radiation therapy and immunotherapy will be discussed. Focus is set on combination of radio(chemo)therapy (RCT) with immune checkpoint inhibitors, growth factor inhibitors, and chimeric antigen receptor T-cell therapy. Well-deliberated combination of RCT with selected immune therapies and growth factor inhibitors bear the great potential to further improve anti-cancer therapies.

SUBMITTER: Derer A

PROVIDER: S-EPMC4597129 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses - Pre-Clinical Evidence and Ongoing Clinical Applications.

Derer Anja A Deloch Lisa L Rubner Yvonne Y Fietkau Rainer R Frey Benjamin B Gaipl Udo S US

Frontiers in immunology 20151008

Radiotherapy (RT) primarily aims to locally destroy the tumor via the induction of DNA damage in the tumor cells. However, the so-called abscopal, namely systemic and immune-mediated, effects of RT move over more and more in the focus of scientists and clinicians since combinations of local irradiation with immune therapy have been demonstrated to induce anti-tumor immunity. We here summarize changes of the phenotype and microenvironment of tumor cells after exposure to irradiation, chemotherape ...[more]

PMID: 26500646

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Project description:Simple Summary Despite recent advances in understanding the molecular biology of tumors, obstacles still exist in the treatment of patients affected by rectal cancer. Recent evidence shows that ionizing radiation may have profound immunostimulatory effects, hinting at the possibility of exploiting radiotherapy to boost anti-tumor immunity. A bulk of work in pre-clinical tumor models have highlighted the potential benefit of this approach. Following these results, a few clinical trials are now evaluating the combination of radiotherapy and immune checkpoint inhibition. Remarkably, encouraging safety and toxicity profiles from these studies indicate that radio-immunotherapy combinations could represent a valid opportunity for rectal cancer patients. Yet, the biological and clinical impact of a radio-immunotherapy combination in rectal cancer remains unclear and further studies need to be performed to optimize the effect of these combinations. Abstract Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

Project description:Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.

Dataset Information

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses - Pre-Clinical Evidence and Ongoing Clinical Applications.

Publications

Radio-Immunotherapy-Induced Immunogenic Cancer Cells as Basis for Induction of Systemic Anti-Tumor Immune Responses - Pre-Clinical Evidence and Ongoing Clinical Applications.

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