HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability

Kawazu, Masahito; Ueno, Toshihide; Saeki, Koichi; Sax, Nicolas; Togashi, Yosuke; Kaneseki, Takayuki; Chida, Keigo; Kishigami, Fumishi; Sato, Kazuhito; Kojima, Shinya; Otsuka, Masafumi; Kawazoe, Akihito; Nishinakamura, Hitomi; Maeda, Yasuhiro; Yamamoto, Yasutake; Yamashita, Kazuo; Inoue, Satoshi; Tanegashima, Tokiyoshi; Matsubara, Daisuke; Tane, Kenta; Tanaka, Yosuke; Iinuma, Hisae; Hashiguchi, Yojiro; Hazama, Shoichi; Khor, Seik‐Soon; Tokunaga, Katsushi; Tsuboi, Masahiro; Niki, Toshiro; Eto, Masatoshi; Shitara, Kohei; Torigoe, Toshihiko; Ishihara, Soichiro; Aburatani, Hiroyuki; Haeno, Hiroshi; Nishikawa, Hiroyoshi; Mano, Hiroyuki

doi:10.1053/j.gastro.2021.10.010

Cited by 40 publications

(36 citation statements)

References 41 publications

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“…Additionally, Immunity_H had higher levels of HLA genes expression and immune cells infiltration than Immunity_L, indicating that Immunity_H had stronger immunogenicity. It has been reported that the expressions of HLA genes play an important role in antitumor activity and in the recognition and elimination of cancer cells [ 30 , 31 ]. Then we visualized the DEGs and DEIGs in Immunity_H and Immunity_L, and it could be seen that the expressions of immune-related genes were found to be significantly different in the two groups.…”

Section: Discussionmentioning

confidence: 99%

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Liang

Chen

et al. 2022

Journal of Immunology Research

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Background. Immunity exerts momentous functions in the progression and treatment of kidney renal clear cell carcinoma (KIRC). A better understanding of the relationship between KIRC and immunity may make a great contribution to evaluating the prognosis and immune-related therapeutic response of KIRC. Methods. A series of information such as RNA sequence, clinical data, and tumor mutation burden (TMB) of KIRC patients were downloaded through The Cancer Genome Atlas (TCGA). Next, combining the survival information and gene expression data of TCGA and Gene Expression Omnibus (GEO), we established an immune gene-related prognosis model (IGRPM) and analyzed it. Then we constructed a nomogram which was convenient for clinicians to judge the prognosis of KIRC. Last but not the least, the expressions of some genes used to construct IGRPM in early KIRC, and adjacent normal tissues were verified through real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Perl (strawberry-perl-5.30.0.1-64bit), R software (4.0.3), and GraphPad Prism 7 were used to process the relevant data. Results. The single-sample gene set enrichment analysis (ssGSEA) showed that there were significant differences in StromalScore, ImmuneScore, ESTIMATEScore, TumorPurity, 22 kinds of human immune cells infiltration, and HLA genes expression between high immunity group (Immunity_H) and low immunity group (Immunity_L). The Immunity_H expressed more immune-related genes and enriched more immune-related functions than the Immunity_L. In addition, compared with the low-risk group, the high-risk group had worse survival outcome and higher TMB. Combining IGRPM-based risk characteristic and TMB, we found that low-TMB + low-risk was the most beneficial to the survival outcome of KIRC patients. The risk characteristic based on IGRPM could be used as an independent prognostic factor for KIRC, and the nomogram constructed for evaluating the prognosis of KIRC showed excellent predictive potential. The RT-qPCR results suggested that not all the genes used to construct IGRPM showed differential expression in early KIRC compared with adjacent normal tissues, but all these genes had significant influence on the prognosis of KIRC. Conclusion. These comprehensive immune assessments and survival predictions, integrating multiple aspects of data and clinical information, can provide additional value to the current Tumor Node Metastasis staging system for risk stratification of KIRC and may facilitate the development of KIRC immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Liang

Chen

et al. 2022

Journal of Immunology Research

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“…Besides, the expression of some human leukocyte antigens (HLAs) was lowly expressed in HS, which was also consistent with the results of fewer infiltration of pro-inflammation immune cells in HS ( Figure 7F ). A plenty of studies have confirmed that impediments to processing HLA would hinder the identification, migration, and infiltration ability of tumor-infiltrating lymphocytes (TILs), thus facilitating the proliferation and invasion of malignancy ( Dong et al, 2021 ; Maggs et al, 2021 ; Kawazu et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Cao

Zhu

et al. 2022

Front. Genet.

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Hypoxia, a typical hallmark of numerous tumors, indicates poor infiltration of antitumor lymphocytes, as well as facilitates the development, progression, and drug resistance of malignant cells. Here, the present research was performed to identify novel hypoxia-related molecular markers and their correlation to the tumor immune microenvironment (TIME) in colon cancer. The expression of hypoxia-related gene signature was extracted from The Cancer Genome Atlas (TCGA) COAD cohort. Based on this signature, a risk score model was constructed using the Lasso regression model. Its discrimination ability and stability were validated in another independent cohort (GSE17536) from Gene Expression Omnibus (GEO) database. Moreover, molecular biology experiments (quantitative real-time PCR and multiple immunohistochemistry) were performed to validate the results of bioinformatics analyses. Three hub genes, including PPFIA4, SERPINE1, and STC2, were chosen to build the risk score model. All of these genes were increasingly expressed in the hypoxia subgroup (HS). Compared with the normoxia subgroup (NS), HS had worse pathological features (T, N, M, and stage) and overall survival (OS), more expression of immune checkpoint molecules, poorer infiltration of some pro-inflammation immune cells (CD4+ T cells and CD8+ T cells), and enriched infiltration of M0/M2 macrophages. After the risk model was proven to be valuable and stable, a nomogram was built based on this model and some clinicopathological factors. Moreover, it had been identified that three hub genes were all increasingly expressed in hypoxic conditions by quantitative real-time PCR (qPCR). The results of multiple immunohistochemistry (mIHC) also showed that higher expression of hub genes was associated with poorer infiltration of pro-inflammation immune cells (CD8+ T cells and M1 macrophages) and richer infiltration of anti-inflammation immune cells (Treg cells and M2 macrophages). In conclusion, the present study uncovered the relations among hypoxia, TIME, and clinicopathological features of colon cancer. It might provide new insight and a potential therapeutic target for immunotherapy.

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“…One of the possible mechanisms under this observation is immune evasion caused by mutations in genes coding components of class I MHC. Although there is no study so far investigating this topic in EPs and EPCs, studies with colorectal cancers have revealed that in tumours with high microsatellite-instability, the expression of HLA-A , HLA-B , and HLA-C were decreased and incidence of mutations in B2M were increased 44 . HLA-A , HLA-B , and HLA-C encode the alpha chain of class I MHC and B2M encodes the beta chain of class I MHC, both enabling the peptide to be presented to specific receptors on the surface of cytotoxic T cells 44 .…”

Section: Discussionmentioning

confidence: 99%

“…Although there is no study so far investigating this topic in EPs and EPCs, studies with colorectal cancers have revealed that in tumours with high microsatellite-instability, the expression of HLA-A , HLA-B , and HLA-C were decreased and incidence of mutations in B2M were increased 44 . HLA-A , HLA-B , and HLA-C encode the alpha chain of class I MHC and B2M encodes the beta chain of class I MHC, both enabling the peptide to be presented to specific receptors on the surface of cytotoxic T cells 44 . Also in non-small cell lung cancer, a high neoantigen burden was associated with loss of heterozygosity in HLA 45 .…”

Section: Discussionmentioning

confidence: 99%

“…Also in non-small cell lung cancer, a high neoantigen burden was associated with loss of heterozygosity in HLA 45 . These immune evasion by tumours with high mutation burden are hypothesized to be the result of gene mutations that indirectly decrease the expression of the genes 44 . Additionally, mutations resulting in upregulation of WNT signalling have been proven to be associated with lower T-cell density in colorectal cancer 46 and in melanoma 47 .…”

Section: Discussionmentioning

confidence: 99%

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UV-induced local immunosuppression in the tumour microenvironment of eccrine porocarcinoma and poroma

Puttonen

Isola

Ylinen³

et al. 2022

Sci Rep

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Eccrine porocarcinoma (EPC) is a rare malignant adnexal tumour of the skin. Part of EPCs develop from their benign counterpart, poroma (EP), with chronic light exposure and immunosuppression hypothesized to play a role in the malignant transformation. However, the impact of chronic light exposure on the microenvironment of EPCs and EPs has not been investigated yet. Although the clinical relevance of tumour infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) has been established in various tumours, their distribution and significance in EPCs and EPs is still poorly understood. We characterized the distribution of TILs and TLSs using CD3, CD4, CD8, CD20 immunohistochemistry in a cohort of 10 EPCs and 49 EPs. We then classified our samples using solar-elastosis grading, analyzing the influence of ultraviolet (UV) damage on TIL density. A negative correlation between UV damage and TIL density was observed (CD4 r = −0.286, p = 0.04. CD8 r = −0.305, p = 0.033). No significant difference in TIL density was found between EPCs and EPs. TLS was scarse with the presence rate 10% in EPCs and 8.3% in EPs. The results suggest that UV has an immunosuppressive effect on the microenvironment of EPCs and EPs.

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HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability

Cited by 40 publications

References 41 publications

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

UV-induced local immunosuppression in the tumour microenvironment of eccrine porocarcinoma and poroma

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