A pan-cancer study of PD-1 and CTLA-4 as therapeutic targets

Abstract

Background: Immunotherapy is a new and powerful weapon against tumors, represented by inhibitors of programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4). This study aimed to determine the similarities and differences between PD-1 and CTLA-4 in 33 cancers in The Cancer Genome Atlas (TCGA) and the impact of subtypes of the immune environment on tumor production and treatment.Methods: From the Xena browser, we downloaded TNM stage, immune subtypes, and tumor microenvironment scores for 33 tumors from TCGA. Expression of CTLA-4 and PD-1 in normal and tumor samples were compared for various tumors with normal tissue sample sizes greater than five. The relationship between expression and overall survival was investigated using one-way Cox analysis. The immune scores of 33 tumors were assessed using ESTIMATE prediction software to predict the degree of immune cell infiltration across tumors and calculate the correlation between PD-1 and CTLA-4 expression with the tumor microenvironment and tumor stem cells. We also examined the correlation between genes and drug sensitivity.Results: PD-1 and CTLA-4 were highly expressed in breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), and kidney renal clear cell carcinoma (KIRC) (P<0.05), highly correlated with immune subtypes C2 (IFN-γ-dominant) and C6 (TGF-β-dominant), and positively correlated with tumor microenvironmental immune scores (P<0.05). In renal clear cell carcinoma, PD-1 and CTLA-4 expression was positively correlated with clinical stage and microenvironmental score (r>0.7, P<0.05). Conclusions:The finding that PD1 and CTLA-4 are associated with the prognosis of most tumour patients and are closely related to the tumour microenvironment is of great value and provides a research direction for the screening of populations benefiting from immunotherapy.

Differences in Co-Expression of T Cell Co-Inhibitory and Co-Stimulatory Molecules with PD-1 Across Different Human Cancers

“…The observed association between PD-1 and CTLA-4 expression might be partially attributed to the PD-1 receptor's classification within the CD28/CTLA-4 family [6]. This study's findings mirror those of the previous research, which observed parallel expression levels of CTLA-4 and PD-1 in tumor tissues, markedly exceeding those in normal tissues in patients with urothelial carcinoma [59].…”

Pan-Cancer Pyroptosis Analyses Identified Novel Immunology and Chemotherapy-Related Prognostic Signatures in Cancer Subtypes

“…Thus, our data provided a novel sight that these mutations might affect tumor progression and patients' prognosis through pyroptosis-related mechanisms. Immune checkpoint molecules such as CTLA-4, PD-1, and PD-L1 have been validated as targets in cancer immunotherapy, but few studies have explored their roles in cancer prognosis [ 38 – 40 ]. We discovered that the expression of immune checkpoint molecules correlated with π signature differentially between the cancer subtypes (Figures 5(c) and 5(d) ).…”

Tumor immune microenvironment and the current immunotherapy of cholangiocarcinoma (Review)

“…CCA tumors with a high PD-L1 expression tend to display more aggressive features and shorter survival times ( 124 , 125 ). CTLA-4 has also been observed to be upregulated in CCA, and of note, a significant positive correlation exists between the expression levels of PD-1 and CTLA-4 ( 126 ). An increased expression of CTLA-4 in TILs has been shown to be associated with malignant characteristics and poor survival outcomes in iCCA.…”