Necroptosis in Immuno-Oncology and Cancer Immunotherapy

Abstract

Immune-checkpoint blockers (ICBs) have revolutionized oncology and firmly established the subfield of immuno-oncology. Despite this renaissance, a subset of cancer patients remain unresponsive to ICBs due to widespread immuno-resistance. To “break” cancer cell-driven immuno-resistance, researchers have long floated the idea of therapeutically facilitating the immunogenicity of cancer cells by disrupting tumor-associated immuno-tolerance via conventional anticancer therapies. It is well appreciated that anticancer therapies causing immunogenic or inflammatory cell death are best positioned to productively activate anticancer immunity. A large proportion of studies have emphasized the importance of immunogenic apoptosis (i.e., immunogenic cell death or ICD); yet, it has also emerged that necroptosis, a programmed necrotic cell death pathway, can also be immunogenic. Emergence of a proficient immune profile for necroptosis has important implications for cancer because resistance to apoptosis is one of the major hallmarks of tumors. Putative immunogenic or inflammatory characteristics driven by necroptosis can be of great impact in immuno-oncology. However, as is typical for a highly complex and multi-factorial disease like cancer, a clear cause versus consensus relationship on the immunobiology of necroptosis in cancer cells has been tough to establish. In this review, we discuss the various aspects of necroptosis immunobiology with specific focus on immuno-oncology and cancer immunotherapy.

Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

“…Moreover, Treg with high expression of CD25 molecules, which is defined as α-chain receptor for IL-2, are mostly responsible for the utilization of IL-2-the cytokine essential for the proper functioning of cytotoxic lymphocytes. In various types of cancer, the high infiltration by regulatory T lymphocytes is associated with poor survival and could predict tumor progression after immune checkpoint inhibitors therapy [20][21][22].…”

The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death

“…Based on its pivotal role in cancer biology, necroptosis has appeared as a new target for cancer treatment; an increasing number of therapeutic agents have shown potential in counteracting tumor growth and recurrence by stimulating or controlling necroptosis [ 155 ]. Necroptosis is determined by both the induction of mitochondrial uncoupling proteins and the blocking of oxidative phosphorylation in CSCs [ 156 ]. Necroptosis is also related to the ALDH family, which may represent a potential therapeutic target for CSCs ( Figure 1 B) [ 157 ].…”

Commentary: A journey of a thousand miles begins with a single step

“…Necroptosis has been described as a relevant factor in a variety of diseases. 2,3 In this issue of the Journal, Ueda and colleagues 4 report on the efficacy of necrosulfonamide, a mixed-lineage kinase domain-like protein inhibitor, in a rat pulmonary ischemia-reperfusion injury model. The number of necroptotic cells in the lungs was significantly decreased in the necrosulfonamide study group.…”