Immunogenomics Analysis Reveals that TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer

Abstract

Although immunotherapy continues to demonstrate efficacy in a variety of refractory cancers, currently, no any immunotherapeutic strategy is clinically used for gastric cancer (GC) except its microsatellite instable subtype. Thus, it is important to identify molecular biomarkers for predicting the responders to GC immunotherapy. TP53 mutations frequently occur in GC and are associated with unfavorable clinical outcomes in GC. We performed a comprehensive characterization of the associations between TP53 mutations and immune activities in GC based on two large-scale GC cancer genomics data. We compared expression and enrichment levels of 787 immune-related genes and 23 immune gene-sets among TP53-mutated GCs, TP53-wildtype GCs, and normal tissue, and explored the correlations between p53-mediated pathways and immune activities in GC. Strikingly, almost all analyzed immune gene-sets were significantly downregulated in enrichment levels in TP53-mutated GCs compared to TP53-wildtype GCs. These less active immune pathways and cell types in TP53-mutated GCs included 15 immune cell types and function, tumor-infiltrating lymphocytes, regulatory T cells, immune checkpoint, cytokine and cytokine receptor, human leukocyte antigen, pro-inflammatory, and parainflammation. Moreover, we identified a number of p53-mediated pathways and proteins that were significantly associated with immune activities in GC. Furthermore, we demonstrated that the TP53 mutation itself could result in the depressed immune activities in GC and other cancer types. We revealed that chromosomal instability was an important mechanism for the depressed tumor immunity in TP53-mutated cancers. Finally, we showed that immune cell infiltration and immune activities were likely positively associated with survival prognosis in GC. Our findings suggest that p53 may play an important role in activating tumor immunity in GC and other cancer types and that the TP53 mutation status could be useful in stratifying cancer patients responsive to a certain immunotherapy.

Figure 1

TP53-mutated GCs likely have the depressed expression of immune cell types and functional marker, TILs, and immune checkpoint genes compared to TP53-wildtype GCs. (A) Heat map for expression levels of immune cell types and functional genes in TP53-mutated and TP53-wildtype GCs. (B). Heat map for expression levels of TILs genes in TP53-mutated and TP53-wildtype GCs. (C) A number of important immune checkpoint genes show significantly lower expression levels in TP53-mutated GCs than in TP53-wildtype GCs in TCGA. *: P < .05, **: P < .01, ***: P < .001, ****: P < .0001, and it applies to all the following box charts.

Figure 1

TP53-mutated GCs likely have the depressed expression of immune cell types and functional marker, TILs, and immune checkpoint genes compared to TP53-wildtype GCs. (A) Heat map for expression levels of immune cell types and functional genes in TP53-mutated and TP53-wildtype GCs. (B). Heat map for expression levels of TILs genes in TP53-mutated and TP53-wildtype GCs. (C) A number of important immune checkpoint genes show significantly lower expression levels in TP53-mutated GCs than in TP53-wildtype GCs in TCGA. *: P < .05, **: P < .01, ***: P < .001, ****: P < .0001, and it applies to all the following box charts.

Figure 2

TP53-mutated GCs likely have the depressed expression of CCR and HLA genes compared to TP53-wildtype GCs. (A) Comparison of enrichment levels of the CCR gene-set between TP53-mutated and TP53-wildtype GCs. (B) A number of HLA genes show significantly lower expression levels in TP53-mutated GCs than in TP53-wildtype GCs.

Figure 3

Immune-related pathways that are downregulated in TP53-mutated GCs compared to TP53-wildtype GCs by the gene-set enrichment analysis.

Figure 4

TP53-mutated GCs are likely to be chromosomally instable, and chromosomal instability is associated with depressed immune activities in cancer. (A) TP53-mutated GCs harbor a significantly higher proportion of CIN samples than TP53-wildtype GCs. (B) TP53-mutated GCs had much more genes with copy number alteration than TP53-wildtype GCs. In each chromosome, the left bar is for the TP53-mutated GC, and the right bar is for the TP53-wildtype GC that is surrounded by a pane. (C) CCR genes that show higher frequencies of copy number alteration in TP53-mutated GCs than in TP53-wildtype GCs. The CCR genes with “*” ahead have higher frequencies of copy number gain, and the others have higher frequencies of copy number loss in TP53-mutated GCs than in TP53-wildtype GCs. (D) Most of the immune gene-sets show significantly lower enrichment levels in CIN cancers than in GS cancers. STAD, stomach adenocarcinoma; COAD, colon adenocarcinoma; NS, not significant. *: P < .05, **: P < .01, ***: P < .001, ****: P < .0001.

Figure 4

TP53-mutated GCs are likely to be chromosomally instable, and chromosomal instability is associated with depressed immune activities in cancer. (A) TP53-mutated GCs harbor a significantly higher proportion of CIN samples than TP53-wildtype GCs. (B) TP53-mutated GCs had much more genes with copy number alteration than TP53-wildtype GCs. In each chromosome, the left bar is for the TP53-mutated GC, and the right bar is for the TP53-wildtype GC that is surrounded by a pane. (C) CCR genes that show higher frequencies of copy number alteration in TP53-mutated GCs than in TP53-wildtype GCs. The CCR genes with “*” ahead have higher frequencies of copy number gain, and the others have higher frequencies of copy number loss in TP53-mutated GCs than in TP53-wildtype GCs. (D) Most of the immune gene-sets show significantly lower enrichment levels in CIN cancers than in GS cancers. STAD, stomach adenocarcinoma; COAD, colon adenocarcinoma; NS, not significant. *: P < .05, **: P < .01, ***: P < .001, ****: P < .0001.

Figure 4

TP53-mutated GCs are likely to be chromosomally instable, and chromosomal instability is associated with depressed immune activities in cancer. (A) TP53-mutated GCs harbor a significantly higher proportion of CIN samples than TP53-wildtype GCs. (B) TP53-mutated GCs had much more genes with copy number alteration than TP53-wildtype GCs. In each chromosome, the left bar is for the TP53-mutated GC, and the right bar is for the TP53-wildtype GC that is surrounded by a pane. (C) CCR genes that show higher frequencies of copy number alteration in TP53-mutated GCs than in TP53-wildtype GCs. The CCR genes with “*” ahead have higher frequencies of copy number gain, and the others have higher frequencies of copy number loss in TP53-mutated GCs than in TP53-wildtype GCs. (D) Most of the immune gene-sets show significantly lower enrichment levels in CIN cancers than in GS cancers. STAD, stomach adenocarcinoma; COAD, colon adenocarcinoma; NS, not significant. *: P < .05, **: P < .01, ***: P < .001, ****: P < .0001.

Figure 5

The p53-mediated pathways and proteins show significant correlations with immune activities in GC. (A) All the immune gene-sets (except cancer testis antigen) show negative correlations with the cell cycle pathway, and positive correlations with the other p53-mediated pathways. B. The differentially expressed proteins between TP53-mutated and TP53-wildtype GCs show significant expression correlations with immune infiltration scores in GC.

Figure 5

The p53-mediated pathways and proteins show significant correlations with immune activities in GC. (A) All the immune gene-sets (except cancer testis antigen) show negative correlations with the cell cycle pathway, and positive correlations with the other p53-mediated pathways. B. The differentially expressed proteins between TP53-mutated and TP53-wildtype GCs show significant expression correlations with immune infiltration scores in GC.

Figure 6

Immune activities are positively associated with survival prognosis in TP53-mutated and TP53-wildtype GCs. A. Kaplan–Meier survival curves show that elevated enrichment of immune gene-sets is associated with better survival prognosis in TP53-mutated and TP53-wildtype GCs (log-rank test, unadjusted P-value <0.05). B. Kaplan–Meier survival curves show that elevated expression of immune genes is associated with better survival prognosis in TP53-mutated and TP53-wildtype GCs (log-rank test, unadjusted P-value <0.05). C. Kaplan–Meier survival curves show that a higher degree of immune cell infiltration is associated with better survival prognosis in TP53-mutated GCs (log-rank test, unadjusted P-value <0.05).

Figure 6

Immune activities are positively associated with survival prognosis in TP53-mutated and TP53-wildtype GCs. A. Kaplan–Meier survival curves show that elevated enrichment of immune gene-sets is associated with better survival prognosis in TP53-mutated and TP53-wildtype GCs (log-rank test, unadjusted P-value <0.05). B. Kaplan–Meier survival curves show that elevated expression of immune genes is associated with better survival prognosis in TP53-mutated and TP53-wildtype GCs (log-rank test, unadjusted P-value <0.05). C. Kaplan–Meier survival curves show that a higher degree of immune cell infiltration is associated with better survival prognosis in TP53-mutated GCs (log-rank test, unadjusted P-value <0.05).

Figure 7

TP53-mutated cancers likely have decreased immune activities compared to TP53-wildtype cancers. (A) All the immune gene-sets (except CTA) likely have lower enrichment levels in TP53-mutated GCs than in TP53-wildtype GCs. Lauren_class, the Lauren classification of GC; Mol_subtype, the molecular classification of GC by TCGA. (B) TP53-mutated cancers have the significantly lower degree of immune infiltration than TP53-wildtype cancers in various cancer types. (C) TP53 mutations may disrupt the functions of wildtype p53 that maintain genome stability, and result in decreased tumor immunity in cancer. HNSC, head and neck squamous cell carcinoma; UCEC, uterine corpus endometrial carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; LUSC, lung squamous cell carcinoma; GBM, glioblastoma multiforme; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma.

Figure 7

TP53-mutated cancers likely have decreased immune activities compared to TP53-wildtype cancers. (A) All the immune gene-sets (except CTA) likely have lower enrichment levels in TP53-mutated GCs than in TP53-wildtype GCs. Lauren_class, the Lauren classification of GC; Mol_subtype, the molecular classification of GC by TCGA. (B) TP53-mutated cancers have the significantly lower degree of immune infiltration than TP53-wildtype cancers in various cancer types. (C) TP53 mutations may disrupt the functions of wildtype p53 that maintain genome stability, and result in decreased tumor immunity in cancer. HNSC, head and neck squamous cell carcinoma; UCEC, uterine corpus endometrial carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; LUSC, lung squamous cell carcinoma; GBM, glioblastoma multiforme; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma.