Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

Abstract

Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of 'eat me' signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…1 However, meanwhile it is well accepted that immune mechanisms contribute to the therapeutic outcome and that the mode of tumor cell death determines if and to which extent irradiation converts the tumor into an in situ vaccine. 2–4 Apart from tumor antigens which need to be made accessible to the immune system, the presence of adjuvants orchestrating the recruitment, differentiation, and activation of antigen-presenting cells (APCs) in the tumor microenvironment is of pivotal importance for the successful priming of anti-tumor immunity. 5,6 In this regard, tumor cells undergoing immunogenic forms of cell death are known to release damage-associated molecular patterns (DAMPs), including heat shock protein 70 (HSP70), high mobility group box1 (HMGB1), and ATP, thereby supporting the recruitment and maturation of APCs.…”

Dying cell recognition shapes the pathophysiology of cell death

“…Immune responses against dead-cell antigen result from a combination of antigenicity and adjuvanticity provided by DAMPs. [4][5][6] As an overarching leitmotif, cell death hence has major consequences for normal tissue homeostasis, stress responses, inflammation and antimicrobial as well as anticancer immune responses, as this is clearly illustrated in this special issue of Cell Death & Differentiation. How can we link cell death then to pathophysiology?…”

“…5 Nonetheless, the simple equation that apoptosis would be an anti-inflammatory and nonimmunogenic event, contrasting with necrosis that would be proinflammatory and potentially immunogenic, constitutes a hitherto inadmissible oversimplification. 6,11,12 At a second level, the surface exposure and release of a vast collection of cell danger-associated molecular patterns (CDAMPs) shape the response to stressed, dying and dead cells. Such CDAMPs include an ever-expanding list of 'findme' signals (also called chemotactic signals) that attract specific leukocyte populations, 13 'keep-out' signals (also called chemorepellents) that repel other leukocyte types, 'eatme' signals that stimulate phagocytosis in different ways, 14,15 'don't eat me' signals that avoid phagocytosis 15 and a collection of DAMPs that are often proteins or nucleic acids, which can only be fully released if the plasma membrane bursts, 6,11,12 as well as anti-inflammatory factors that mitigate local tissue reactions.…”

“…6,11,12 At a second level, the surface exposure and release of a vast collection of cell danger-associated molecular patterns (CDAMPs) shape the response to stressed, dying and dead cells. Such CDAMPs include an ever-expanding list of 'findme' signals (also called chemotactic signals) that attract specific leukocyte populations, 13 'keep-out' signals (also called chemorepellents) that repel other leukocyte types, 'eatme' signals that stimulate phagocytosis in different ways, 14,15 'don't eat me' signals that avoid phagocytosis 15 and a collection of DAMPs that are often proteins or nucleic acids, which can only be fully released if the plasma membrane bursts, 6,11,12 as well as anti-inflammatory factors that mitigate local tissue reactions. 1,15 In a way, agonizing cells 'choose' by which phagocyte they will be engulfed, in which way their clearance will occur and what the consequences on the microenvironment will be.…”

“…Moreover, the DAMPs exposed on or released from dying cells determine the activation and differentiation of the engulfing cells (including M1/M2 polarity or maturation of dendritic cell precursors) [15][16][17] and the possible activation of bystander cells that participate to inflammatory and immunological reactions. 5,6 Viewed in this manner (Figure 1), it is easily comprehensible that multiple distinct molecular pathways must contribute to normal organismal maintenance and the reestablishment of an equilibrium state after local or generalized tissue damage. Hence, mutations or alterations in the expression level of genes that affect cell death signaling cascades, as well as the optimal function of clearance systems (which likely involve many genes/proteins involved in autophagy as well), 18 may have deleterious consequences by causing overshooting responses (and hence autoinflammatory and autoimmune disease) 19 or their functional failure.…”