TP53 Mutation as Potential Negative Predictor for Response of Anti-CTLA-4 Therapy in Metastatic Melanoma

Abstract

TP53 has been proved to be associated with cytotoxic T-cell induced apoptosis, however, the association between TP53 and the benefit of immunotherapy in melanoma has not been studied. In the present study, we examined the relationship between TP53 mutation and response to CTLA-4 blockade in metastatic melanoma by analyzing the data from one public cohort consisting of 110 patients with metastatic melanoma. The sequencing, mRNA and survival data of 368 patients with skin melanoma from The Cancer Genome Atlas (TCGA) was used to explore the underlying mechanism. TP53 mutation was associated with significant poorer progression-free survival (HR, 2.25; 95% CI, 1.15–4.37; P = 0.014), poorer overall survival (HR, 2.05; 95% CI, 1.02–4.13; P = 0.040) and trend of poorer response (OR, 0.20; 95% CI, 0.02–1.62; P = 0.131). The correlations were significant in multivariate analysis including lactate dehydrogenase, tumor mutational burden and tumor stage (P < 0.05). In TCGA, no association was observed between TP53 mutation and survival (P = 0.55). The mRNA expression of FAS was lower in patients with TP53 mutation than TP53 wild-type. Our findings suggest that TP53 mutation is a potential negative predictor of metastatic melanoma treated with CTLA-4 blockade.

Characteristics and prognostic significance of profiling the peripheral blood T‐cell receptor repertoire in patients with advanced lung cancer

“… In addition, lower clonotype and diversity were also present in patients with mutated TP53 (Supporting Information Fig. S9), which was reported recently to be a negative predictor for response to ICB treatment …”

“…S9), which was reported recently to be a negative predictor for response to ICB treatment. 36 Taken together, these findings indicate that the TCR repertoire is closely associated with several clinical characteristics, and high repertoire diversity reflects favorable immune status in patients with lung cancer, which may be exploited to direct anticancer treatment.…”

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

“…The Friends and QuIP initiatives for TMB harmonization recommended to include as much relevant genetic and molecular information as possible in these panels, to avoid the need to re-biopsy the patient for further information. In line with this recommendation, we propose to also include in gene panels for TMB quantification other potential immunotherapy biomarkers but also negative predictors of immunotherapy response [69,70] and variants predisposing to adverse reaction to immunotherapy [71,72]. These and other recommendations which emerge from the studies reviewed here, including the one from the TMB Harmonization Working Group, are summed up in Additional file 6: Table S6.…”

The Immune Microenvironment in Penile Cancer and Rationale for Immunotherapy

“…In addition, Xiao et al studied in metastatic melanoma patients the relationship between TP53 mutation and the response to anti-CTLA-4 therapy. The authors reported that increased TP53 expression is significantly associated with poor response, poor progression-free survival, and poor overall survival, suggesting it as a negative predictor for response to CTLA-4 blockade [ 93 ].…”