Immunogenic cancer cell death: how it can be exploited

Skivka L.M.

L. Skivka

Taras Shevchenko Kyiv National University, Kyiv, Ukraine

When considering normal, non-transformed cells, it is commonly assumed that the immunological consequences of cell death follow a classical dichotomy of immunogenic necrosis versus non-immunogenic (or even tolerogenic) apoptosis. However, recent studies have revealed that apoptotic tumor cells induced by ionizing irradiation, anthracyclines and some other cytotoxic agents are able to induce a potent immune response in vivo. This led to the hypothesis that cell stress or death may result in the release of endogenous danger signals that act as adjuvants to stimulate an immune response. Some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express “danger” and “eat me” signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. These endogenous danger signals (or alarmins) promote activation of innate immune cells and recruitment and activation of antigen-presenting cells engaged in host defense through pattern recognition receptors such as the TLRs, many of which have a key role in the detection of pathogens. In addition, these danger associated molecules act broadly with many other immunostimulatory molecules (endogenous and exogenous including pathogen associated molecular patterns or PAMP) to amplify their activity in a synergistic manner. In our investigations we used cytotoxic drug NSC-631570 in combination with PAMP in the treatment of melanoma B16 bearing mice. Our results suggest that bacterial adjuvants synergized with chemotherapy to inhibit tumor growth and significantly augment immune responses. Current evidence suggests that once in the extracellular milieu, alarmins can bind to molecules such PAMP and, depending on its interactions with DNA, can form complexes of varying structure and with a varying the number of components. Here we analyse the current know­ledge and our data to discuss the hypothesis that the formation of extracellular complexes is an important mechanism for generating pro-inflammatory signals during cell death and reverting some of the established immuno-supressive barriers present within the tumor microenvironment, ideally recovering the role of the tumor as an effective immunogenic hub.

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