Cancer immunotherapy is a kind of method to treat cancer by activating the immune system. This kind of therapy adopts the results of cancer immunology research, which is a rapidly developing research direction in oncology.
The immune system plays important roles in cancer development and treatment, and immune activation caused by chronic infection or inflammation is well-known to increase cancer risk. The clinical success of immune checkpoint blockade therapies (ICBs) is limited to a small set of CRCs with high tumor mutational load and tumor infiltrating T cells. Induction of immunogenic cell death (ICD), a type of cell death eliciting an immune response, can therefore help break the immunosuppressive TME, engage the innate components and prime T cell-mediated adaptive immunity for long-term tumor control.
Immunogenic cell death (ICD) refers to the process that tumor cells die when they are stimulated by the outside world, and the process of transforming from non-immunogenicity to immunogenicity, which mediates the body's anti-tumor immune response. When tumor cells undergo ICD, they will produce a series of signal molecules, which are called damage-associated molecular patterns (DAMP), mainly including calreticulin exposed on the cell surface, high mobility group protein 1 (HMGB1) secreted by tumor cells, ATP molecules released by cells, and heat shock proteins (HSP70, HSP90). The DAMPs released during ICD can combine with the pattern recognition receptor PRRs on the surface of DC cells, initiate a series of cytological reactions, and finally activate the innate and adaptive immune responses.
we identified two molecular subtypes by consensus clustering approach based on 96 ICD related genes. Immune analyses indicated that patients with favorable clinical outcomes were in relatively a high level of immune status, and possessed higher stromal score, immune score, ESTIMATE score, whereas lower tumor purity, as compared with patients with poor prognosis. Further functional analyses revealed that expression of ICDRGs was associated with the immune-active microenvironment. Moreover, we constructed and validated a prognostic risk signature based on 11 selected ICD-related genes (ICDRGs) for LUAD patients in the TCGA database, this risk signature showed a high predictive value in terms of OS and might function as an independent prognostic indicator and well verified in 4 independent cohorts from the GEO dataset. Furthermore, we discovered that patients with a low-risk score are more likely to benefit from immunotherapy than that of patients with high-risk scores, which indicating that immune checkpoint blockade therapy may be more appropriate for low-risk patients. Our results may facilitate the development of targeting therapy for LUAD and help the clinicians to make more rational treatment decisions.
In this study, ICDRGs was composed of 11 Immunogenic cell death related genes (BIRC3, ITGA6, SHC1, NEUROD1, EIF2AK3, GLI2, LDHA, VDAC1, HMMR, CCR2 and FUT4), most of these genes were involved in the proliferation, invasion, and differentiation of LUAD cells.
BIRC3 encodes a member of the IAP family of proteins, an inhibitor of an apoptosis-associated proteins family[34]. BIRC3 has been shown to regulate not only caspases and apoptosis, but also cell proliferation, modulates inflammatory signaling and immunity, as well as cell invasion and metastasis[35]. Previous studies have revealed that BIRC3 is an important driving factor to tumor progression in several malignancies[36–38], BIRC3 may serve as a potential biomarker of LUAD, which lower expression associated with a better prognosis in patients with lung cancer [23].
ITGA6, encoding a member of the integrin alpha chain family of proteins[39]. ITGA6 overexpression was found to be promotes lymphangiogenesis and lymphatic metastasis in LUAD via activating the NF-κB signaling pathway[40]. SHC1 has been identified to have effective prognostic and diagnostic biomarker value in multiple cancers[41]. The high SHC1 expression in LUAD patients have a poor prognosis, and EGFR expression was significantly correlated with SHC1 and maybe a a downstream regulatory protein of SHC1 interaction[42]. NEUROD1 involved in several processes, including regulation of apoptotic process, animal organ development, and it regulates expression of the insulin gene, mutations in this gene result in type II diabetes mellitus[43]. as yet, no connection between NEUROD1 and LUAD has been reported. PERK, also known as EIF2AK3, is a type I membrane protein with a serine/threonine cytoplasmic domain located in the endoplasmic reticulum (ER). It is activated under ER stress caused by malfolded proteins. The role of PERK on a physiological level is unclear. GLI2 can cooperate with lncRNA BCAR4 to regulate the viability, invasion and migration of NSCLC, in tumor xenograft assay, si-GLI2 showed the smallest volume[44]. Study showed that by co-culture A549 and H1299 experiment, suppression of LDHA or PDK1 can abrogate the stimulatory signal from cancer cells to fibroblasts and silencing LDHA gene in cancer cells prevent cancer cells migration[45]. VDAC1 has been reported as a cancer therapeutic target in kinds of cancers including NSCLC, VDAC1 is a vital biomarker for tumor growth and cancer proliferation[33, 46]. HMMR is linked to the level of immune infiltration of neutrophils, CD8 + T cells, and CD4 + T cells in LUAD patients[47]. In macrophage and lung cancer cell co-culture cell system, when mice was treated with CCR2 antagonist, the growth and metastasis was inhibited, in human lung cancer samples, tumor macrophage infiltration and CCR2 is reported correlated with tumor stage and metastasis[48]. Study shows FUT4 knockdown can increase cisplatin-cytotoxicity and its silencing can inhibit the proliferation in A549 and H1975 cells by regulating the Akt and FOXO1 signal pathway[49].
It was reported that the immunogenic cell death was closely related to tumor patient’s prognosis[23, 50–53]. For example, in the TCGA training cohort and two GEO validation cohort, patients with high-score of immunogenic cell death had worse prognosis than patients with low-score in ovarian cancer[54]. In uveal melanoma, a 5-gene ICD related genes risk signature was constructed, signature with high score had more immune cell infiltration and a worse prognosis than the low score group[55]. ICD related genes signature was evaluated in many types of cancers, but in LUAD, the research is still not clear. In our study, we constructed a prognosis related signature model and validate it in four GEO data base. To further clarify the mechanism of this model to predict the prognosis of LUAD, we evaluated the PD-L1 expression between high-risk and the low-risk patients, the results indicated that patients with a low-risk score are more likely to benefit from immunotherapy. Besides, we evaluated the association of ICD-related-genes with tumor microenvironment, we found high-risk patients had lower immune score, stromal score, ESTIMATE score and higher tumor purity. Based on the results of the difference analysis and correlation analysis we found that patients with low-score had better long-term survival rates.
In conclusion, based on the database of TCGA we established a ICD genes related risk model containing 11 genes to predict the prognosis of patients with LUAD, which was validated by four independent GEO database. By describing the tumor microenvironment landscape, immune landscape and immune therapy characteristic of these two clustered subgroups, we investigated the potential mechanism of this model for predicting the prognosis of LUAD, which could help clinicians to develop precision treatment for LUAD patients, especially who undergoes immunotherapy and diagnosed with special gene mutations.