Detection of immunogenic cell death and its relevance for cancer therapy

Abstract

Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

Invasive Breast Carcinoma Tumor Size on Core Needle Biopsy: Analysis of Practice Patterns and Effect on Final Pathologic Tumor Stage

“…2 Prior studies examining the mechanistic underpinning of RT largely focused on the DNA-damaging properties and the resultant cell death; however, preclinical and clinical evidence generated over the last decade suggest that RT-induced cell death can also alter the tumor microenvironment (TME) and trigger an anti-tumor inflammatory response. [3][4][5][6] In light of recent clinical successes with immune checkpoint blockade (ICB)-mediated immune modulation in breast cancer together with a growing body of preclinical and clinical data demonstrating synergy between ICB and RT, [7][8][9] the clinical application of ICB with RT is an active area of investigation. Herein, we review the preclinical and clinical rationale for combining RT and ICB in breast cancer, early data from recent clinical trials, and relevant future directions.…”

Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

“…However, local irradiation of the tumor cells will result in both local and systemic immunogenic responses. Although accumulating preclinical evidence indicates that RT-induced ICD is accompanied by the exposure, active secretion, or passive release of numerous DAMPs [ 5 ], it is striking that in the majority of studies only one ICD-associated molecule is studied. A single biomarker can generally not be used to monitor treatment-induced immune responses, and therefore, multiple biomarkers should be studied simultaneously at different time points.…”

“…To date, it has been well-established that RT can also induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of cancer cells and their capacity to generate adjuvant signals [ 5 ]. In particular, RT-induced immunogenic cell death (ICD), which is defined as ‘a form of regulated cell death that is sufficient to activate an adaptive immune response in immunocompetent hosts’ [ 6 ], is known to contribute to the propagation of antitumor immunity [ 4 , 7 , 8 ].…”

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

“…Clinical and preclinical studies indicate that these agents may be particularly relevant to the activation of antitumor immune responses triggered by ICI or other forms of immunotherapy in the context of combinatorial treatment regimens. In this regard, a number of FDA-approved ICD inducers are currently being studied in the oncology setting, especially in combination with immunotherapeutic agents [ 106 ].…”

“…Several evidences indicate that radiation therapy has an abscopal effect causing cancer regression in non-irradiated metastatic sites [ 107 ]. Like chemotherapy, radiation therapy triggers ICD by causing the release of DAMPs and tumor-associated antigens and thereby priming tumor-specific immunity [ 106 ]. Cytosolic DNA released from tumor cells after radiation therapy acts as a DAMP by inducing the production of type I interferon from DCs via cGAS/STING.…”