Cancer type-dependent correlations between TP53 mutations and antitumor immunity

Abstract

Many studies have shown that TP53 mutations play a negative role in antitumor immunity. However, a few studies reported that TP53 mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found that TP53-mutated cancers had significantly higher levels of antitumor immune signatures than TP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast, TP53-mutated cancers had significantly lower antitumor immune signature levels than TP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover, TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) than TP53-wildtype cancers. However, the TMB differences were more marked between TP53-mutated and TP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations between TP53 mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused by TP53 mutations on tumor immunity. Our data suggest that the TP53 mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

Prognosis of Lung Adenocarcinoma Patients With NTRK3 Mutations to Immune Checkpoint Inhibitors

“…The results for the dataset TCGA-LUAD revealed that NAL, TMB and smoking history correlated significantly with the NTRK3 mutation status but that the age, sex, stage, race, and ethnicity did not. Interestingly, we also found that the mutation rate of Tp53 was higher in patients with NTRK3-MT, consistent with prior reports that Tp53 mutations are associated with enhanced antitumor immunity in LUAD (Li et al, 2020). Overall, these results highlight a potential role of NTRK3-MT as a predictive biomarker for ICI treatment.…”

“…For example, clinical studies have confirmed that ICIs do not enhance OS in NSCLC patients with EGFR mutations; in other words, patients with EGFR mutations do not respond well to immunotherapy (Akbay et al, 2013;McGranahan et al, 2016;Lin et al, 2019). A study from Li et al showed that the correlation between Tp53 mutations and tumor immunity differs among tumor types and that the Tp53 mutation status may be a negative predictor for response to ICIs in these cancers (Li et al, 2020). KRAS comutations and TET1 mutations have been demonstrated to be novel predictors for ICI response in different cancer types (Skoulidis et al, 2015;Wu et al, 2019).…”

Leukoplakia and Immunology: New Chemoprevention Landscapes?

“…The relationship between TP53 and immune signature has been confirmed in other recent work by Li et al, indicating the connections between TP53 mutations and anticancer immunity as a consequence of the effect of the altered TMB and tumor aneuploidy level due to TP53 mutations on tumor immunity [71]. In particular, they discovered that, in HNSC, tumor aneuploidy level more strongly affected antitumor immunity than TMB [71]. It is necessary to keep in mind that early mutations in TP53, a frequent finding in leukoplakia as well as in head and neck carcinoma, are related to a copy number genomic instability [72].…”

“…They found that TP53 mutations were present with reduced immune signatures while HRAS mutations were related to increased immune signatures in HNSCC [70]. The relationship between TP53 and immune signature has been confirmed in other recent work by Li et al, indicating the connections between TP53 mutations and anticancer immunity as a consequence of the effect of the altered TMB and tumor aneuploidy level due to TP53 mutations on tumor immunity [71]. In particular, they discovered that, in HNSC, tumor aneuploidy level more strongly affected antitumor immunity than TMB [71].…”

“…The role of immunity in the development of malignant lesions of the oral mucosa might also emphasize the relationship between chronic trauma and the onset of malignancies. Chronic inflammation is considered a risk factor for oral cancer; in this view, Sun et al proposed that immunosuppression due to chronic flogistic processes encourages oral tumorigenesis, rather than initiating it [71].…”