Therapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy?

Abstract

Combinatory treatments using surgery, radiotherapy and/or chemotherapy together with immunotherapy have shown encouraging results for specific subsets of tumors, but a significant proportion of tumors remains unsusceptible. Some of these inconsistencies are thought to be the consequence of an immunosuppressive tumor microenvironment (TME) caused by therapy-induced tumor cell death (TCD). An increased understanding of the molecular mechanisms governing TCD has provided valuable insights in specific signaling cascades activated by treatment and the subsequent effects on the TME. Depending on the treatment variables of conventional chemo-, radio- and immunotherapy and the genetic composition of the tumor cells, particular cell death pathways are activated. Consequently, TCD can either have tolerogenic or immunogenic effects on the local environment and thereby affect the post-treatment anti-tumor response of immune cells. Thus, identification of these events can provide new rationales to increase the efficacy of conventional therapies combined with immunotherapies. In this review, we sought to provide an overview of the molecular mechanisms initiated by conventional therapies and the impact of treatment-induced TCD on the TME. We also provide some perspectives on how we can circumvent tolerogenic effects by adequate treatment selection and manipulation of key signaling cascades.

Keywords: caspase-dependent apoptosis; damage associated molecular pattern (DAMP); immunogenic; immunotherapy; therapy-induced senescence; tolerogenic; tumor cell death; tumor microenvironment (TME).

Figure 1

A schematic overview of the complex pathways regulating cell death. Necroptosis can be triggered by both extrinsic and intrinsic stimuli. The extrinsic pathway can be activated by chemokine, cytokine and death receptors, which leads to the activation of receptor interacting protein (RIP)-kinases. Similar activation is also achieved via intracellular stress. Subsequently, activation of the RIP-complex leads to phosphorylation of mixed lineage kinase domain like pseudokinases (MLKL), which is inhibited by caspase-8 under normal circumstances. MLKL phosphorylation induces a translocation to the cell membrane, which leads to permeabilization of the cell and consequently necroptotic cells death. Senescence is predominantly induced via a cell cycle arrest initiated by p53, but this process can also lead to the senescence associated secretory phenotype (SASP). Moreover, SASP can be induced via extrinsic stimuli that activate the Janus kinase- signal transducer and activator of transcription (JAK-STAT) pathway. Intracellular stress can inhibit the mammalian target of rapamycin (mTOR) pathway, which allows formation of the autophagosome. This formation can be inhibited by pro-apoptotic members of the BCL-2 family but is also able to inhibit caspase cleavage and thereby displays the crosstalk between autophagy and apoptosis. Eventually, after formation of the autophagosome, autophagic cell death is induced. Additionally, apoptosis can be induced by both intrinsic and extrinsic stimuli. Extrinsic stimuli allow cleavage of caspase-8, which can either induce cleavage of the caspase3/7 complex or activate members of the pro-apoptotic BCL-2 family. Activation of caspase3/7 results in caspase dependent apoptosis. However, the BCL-2 proteins can also be activated by intrinsic stimuli or intracellular stress and lead to the mitochondrial outer membrane permeabilization (MOMP), which in turn releases both cytochrome C and apoptosis inducing factors (AIF). Cytochrome C interacts with caspase-9 and subsequently induces caspase-dependent apoptosis via the activation of caspase 3/7. In contrast, AIF facilitates caspase-independent apoptosis by initiation of chromatin condensation and DNA fragmentation. This figure was created by authors using Biorender tools (biorender.com).

Figure 2

Schematic overview of tailoring therapeutic strategies to avoid tolerogenic cell death. (A) Avoiding tolerogenic cell death. Immunogenic cell death can be induced by (1) changing chemotherapeutic agents or (2) changing dose and regimes in radiotherapy. (B) Converting tolerogenic cell death to immunogenic cell death. Immunogenic cell death can be initiate by (1) chemically or (2) virally changing the cell death pathway, (3) chemically inhibiting tolerogenic pathways or (4) chemically stimulate immunogenic cell death. (C) Boosting immunogenic effects. Immunogenicity can be boosted via (1) the introduction of cytokines directly or via the delivery with (2) oncolytic viruses or (3) CAR T cells. (D) Regulating tolerogenic stimuli. Tolerogenic stimuli can be inhibited with (1) antibodies, (2) immune suppressive cells can be forced into differentiation or (3) T cells can be engineered to become resistant to tolerogenic stimuli. This figure was created by authors using Biorender tools (biorender.com).

Figure 3

A schematic overview of inhibitors converting tolerogenic cell death to immunogenic cell death. (A) The pan-caspase inhibitor Z-VAD-fmk inhibits all caspase activity, the subsequent effects are depicted with red dotted lines. Z-VAD-fmk forces extrinsic stimuli to activate the RIP-kinase complex and thereby initiates necroptosis instead of caspase-dependent apoptosis. Intrinsic stimuli remain able to activate the pro-apoptotic BCL-2 family members and subsequently facilitate mitochondrial outer membrane permeabilization (MOMP). Consequently, both apoptosis inducing factors (AIF) and cytochrome C are released, but only AIF is able to induce apoptosis. Therefore, caspase-dependent apoptosis will be inhibited and decreased, and caspase-independent apoptosis will increase. (B) Both Janus kinase- signal transducer and activator of transcription (JAK-STAT) and JAK inhibitors are capable of inhibiting the senescent pathway, depicted in red dotted lines. This reduces the activation of the senescent associated secretory phenotype (SASP) after activation of the extrinsic pathway. In contrast, the intrinsic pathway remains able to induce the SASP via activation of p53. (C) Both nutrient starvation and mammalian target of rapamycin (mTOR) inhibition increase autophagy, by upregulation of the autophagosome. This figure was created by authors using Biorender tools (biorender.com).