From targeted therapy to a novel way: Immunogenic cell death in lung cancer

Abstract

Lung cancer (LC) is one of the most incident malignancies and a leading cause of cancer mortality worldwide. Common tumorigenic drivers of LC mainly include genetic alterations of EGFR, ALK, KRAS, BRAF, ROS1, and MET. Small inhibitory molecules and antibodies selectively targeting these alterations or/and their downstream signaling pathways have been approved for treatment of LC. Unfortunately, following initial positive responses to these targeted therapies, a large number of patients show dismal prognosis due to the occurrence of resistance mechanisms, such as novel mutations of these genes and activation of alternative signaling pathways. Over the past decade, it has become clear that there is no possible cure for LC unless potent antitumor immune responses are induced by therapeutic intervention. Immunogenic cell death (ICD) is a newly emerged concept, a form of regulated cell death that is sufficient to activate adaptive immune responses against tumor cells. It transforms dying cancer cells into a therapeutic vaccine and stimulates long-lasting protective antitumor immunity. In this review, we discuss the key targetable genetic aberrations and the underlying mechanism of ICD in LC. Various agents inducing ICD are summarized and the possibility of harnessing ICD in LC immunotherapy is further explored.

KRTA6AandFA2HAre Hub Genes Associated With Cgas-STING-related Immunogenic Cell Death in Lung Adenocarcinoma

“…The resistance to apoptosis and ICD is the major obstacle for improving the efficiency of LUAD pharmaceutical therapy (17). Various chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy can cause ICD (18).…”

“…The six hub genes, namely, keratin 6A (KRT6A), KRT16, EGF-containing fibulin-like extracellular matrix protein 1 (EFFEMP), lysyl oxidase (LOX), fatty acid 2-hydroxylase (FA2H), and serine palmitoyltransferase 3 (SPTL3), have been reported to be closely related with the prognosis of lung cancer (14)(15)(16)(17)(18)(19). To validate the effect of the above hub genes on the OS of LUAD patients, we performed survival comparative analysis using TCGA database.…”

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…A mitogen-activated protein inhibitor drug, trametinib, could be effective in treating KRAS-mutant lung adenocarcinoma when combined with interleukin-12 by giving rise to ICD through sensitizing cancer cells to ERS and triggering the release of DAMPs ( Wang et al, 2020 ). The EGFR-targeting antibody cetuximab, Bruton’s TKI ibrutinib, anaplastic lymphoma kinase TKI (crizotinib and ceritinib), mesenchymal-epithelial transition factor TKI foretinib, receptor protein TKI lestaurtinib, EGFR-TKI (lapatinib and canertinib), and CDK4/CDK6 inhibitors (abemaciclib and palbociclib) have also been demonstrated to present ICD activity before ( Galluzzi et al, 2015 ; Inoue et al, 2017 ; Pozzi et al, 2016 ; Sagiv-Barfi et al, 2015 ; Schoenwaelder et al, 2021 ; Xu et al, 2022 ) ( Table 1 ). Therefore, they have not been described in detail in this review.…”

“…Carbon iron radiotherapy is an emerging type of ionizing radiation based on 12 C 6+ . In addition to changes in ATP and the phosphorylation level of eIF2α, it leads to higher intranuclear HMGB1 efflux and mRNA level interferon expression in melanoma-bearing mice models compared with X-ray irradiation (Zhou et al, 2022). Proton radiation also presents a stronger tumor-killing effect on multiple human tumor cell lines (such as lung adenocarcinoma, glioma, tongue squamous carcinoma, and nasopharyngeal carcinoma), and has an equal effect to photon rays in inducing CRT exposure (Huang et al, 2019).…”

Immunotherapies inducing immunogenic cell death in cancer: insight of the innate immune system

“…ICD is a promising strategy because it induces long-term efficacy of anticancer drugs through the combination of the direct cancer cell killing and the activation of the antitumour immune system, leading to an anti-tumour immunological memory (3). Some chemotherapies, radiotherapies, and targeted therapies have been shown to induce immunogenic cell death (4)(5)(6). Such ICD inductors have been successfully combined with different types of immunotherapies to promote better outcomes (7,8).…”