Ex vivo– and in vivo–induced dead tumor cells as modulators of antitumor responses

Abstract

Joint application of standard tumor therapies like radiotherapy and/or chemotherapy with immune therapy has long been considered not to fit. However, it has become accepted that immune responses may contribute to the elimination of cancer cells. We present how in vivo-induced tumor cell death by irradiation, chemotherapeutic agents, or hyperthermia can be rendered more immunogenic. High hydrostatic pressure is introduced as an innovative inactivation method for tumor cells used as vaccines. Annexin A5, being a natural occurring ligand for phosphatidylserine that is exposed by dying tumor cells, renders apoptotic tumor cells immunogenic and induces tumor regression. Combinations of irradiation with hyperthermia may also foster antitumor responses. For preparation of autologous tumor cell vaccines, high hydrostatic pressure is suitable to induce immunogenic cancer cell death. Future work will be aimed toward evaluating which combination and chronological sequence of radiotherapy, chemotherapy, hyperthermia, annexin A5, and/or autologous tumor cell vaccines will induce specific and long-lasting antitumor immunity.

Induction of Abscopal Anti-Tumor Immunity and Immunogenic Tumor Cell Death by Ionizing Irradiation - Implications for Cancer Therapies

“…In addition to defining cell death on the basis of signalling pathways it is also of great importance for "onco-immunology" to define it on the basis of its immunological outcome, namely immunogenic or tolerogenic cancer cell death [9,109]. Detailed information about the immunological potential of cell death and other cell death modalities such as autophagy and mitotic catastrophe have been considered elsewhere [8,66].…”

“…The primary goal of standard RT is the local control of tumors and one approach for achieving radiocurability is via the elimination of proliferating (clonogenic) tumor cells. However, it has to be kept in mind that the induction of cell death is safer than merely stopping the proliferation of tumor cells [9]. The forms of tumor cell death that are induced by X-ray will be discussed later.…”

Consensus guidelines for the detection of immunogenic cell death

“…36,37 Upon binding to low density lipoprotein receptorrelated protein 1 (LRP1, also known as CD91), membraneexposed CALR delivers a major phagocytic signal to professional antigen-presenting cells (APCs) such as dendritic cells, de facto improving their capacity to take up dead cells and their corpses. 66,91,[166][167][168][169][170][171][172][173] Interestingly, the phagocytosis-stimulatory effects of CALR is robustly counterbalanced by CD47, which is highly expressed by a large panel of solid and hematopoietic tumors. 166 This latter observation suggests that various neoplasms benefit from avoiding the effects of CALR exposure, perhaps as this prevents the elicitation of an adaptive immune response against the malignant cells that "physiologically" succumb in the course of oncogenesis and tumor progression.…”

Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy

“…118 Also HMGB1 release was detected after HT treatment of tumor cells lines at high temperature of 56 C. 59 The current paradigm of the immunogenicity of HT lies in the action of HSP70 and/or other released heat shock proteins which via TLR4 signaling play the main role in the initiation of tumorspecific immune responses. 111,112,119,120 It has been shown that the combination of HT and RT (X-rays or UVC) induces an inflammatory necrotic tumor death which can be monitored by the release of HMGB1 and HSP70 121,122 and stimulation of DC maturation and release of pro-inflammatory cytokines. 59,123 Currently there are no clinical data on the use of HT-killed tumor cells alone in clinical protocols.…”