Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

Abstract

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Keywords: anti-tumor immunity; immunogenicity; immunotherapy; molecular medicine; oncoimmunology; patient prognosis; translational medicine.

Figure 1

The molecular complexity of immunogenic cell death in cancer. Cancer cells undergoing immunogenic cell death (ICD) emit danger signals for establishing a productive interface with components of the host immune system, including dendritic cells (DCs). DCs exposed to cancer cells succumbing to ICD “prime” the adaptive arm of the immune system, consisting of various effector T-cell populations, which in turn targets therapy-resistant cancer cells. Various molecules are critical for the execution of these processes. The molecular network of ICD-relevant proteins was build using the STRING modeling database (http://string-db.org/) (126).

Figure 2

Population dynamics of antigen-specific T cells during an immune response to infection or cancer. (A) T cells capable of putatively recognizing non-self, pathogen-associated antigens (PAAs) are not exposed to negative selection in the thymus or peripheral organs like lymph nodes. This allows for the constitutive presence of T lymphocytes bearing high-affinity T-cell receptor (TCR) in naïve conditions. Upon infection, these cells undergo robust expansion and acquire potent effector functions, hence driving an immune response that clears the pathogen and PAAs. Finally, PAA-specific T cells undergo contraction along with the establishment of immunological memory. To a limited extent, T cells reacting against PAAs expressed by virus-induced tumors may exhibit similar (although not identical) responses. (B) T cells that may recognize self or close-to-self antigens expressed by virus-unrelated malignancies undergo robust negative selection in the thymus and lymph nodes. Thus, all putative T lymphocytes bearing a high-affinity TCR against tumor-associated antigens (TAAs) are eliminated. However, some leakiness in this process allows for the persistence of TAA-specific T lymphocytes with low-affinity TCR, although at very low precursor frequencies. This is one of the reasons why in some individuals immunosurveillance at some stage fails to impede tumor progression. As malignant lesions progress, the amount of TAAs increases, causing a weak rise in TAA-specific T cells. However, tumor progression is generally coupled with the establishment of robust immunosuppressive networks that potently inhibit such TAA-targeting T cells. In this context, the administration of immunogenic cell death (ICD) according to a schedule that does not lead to lymphodepletion can favor the stimulation of TAA-targeting T cells and (re)instate immunosurveillance. Combining ICD inducers with checkpoint-blocking agents may further boost TAA-targeting immune responses. However, these treatments may not ensure the lifelong persistence of TAA-recognizing T cells, some of which are susceptible to elimination through tolerance mechanisms. Anticancer vaccines may counteract, at least to some extent, such loss. The figure was partly inspired from Baitsch et al. (234).