P2RX7B is a new theranostic marker for lung adenocarcinoma patients

Abstract

Rationale: The characterization of new theranostic biomarkers is crucial to improving the clinical outcome of patients with advanced lung cancer. Here, we aimed at characterizing the P2RX7 receptor, a positive modulator of the anti-tumor immune response, in patients with lung adenocarcinoma. Methods: The expression of P2RX7 and its splice variants was analyzed by RT-qPCR using areas of tumor and non-tumor lung adenocarcinoma (LUAD) tissues on both immune and non-immune cells. The biological activity of P2RX7 was studied by flow cytometry using fluorescent dyes. Bi-molecular fluorescence complementation and confocal microscopy were used to assess the oligomerization of P2RX7. Tumor immune infiltrates were characterized by immunohistochemistry. Results: Fifty-three patients with LUAD were evaluated. P2RX7A, and 3 alternative splice variants were expressed in LUAD tissues and expression was down regulated in tumor versus adjacent non-tumor tissues. The protein retained biological activity only in immune cells. The P2RX7B splice variant was differentially upregulated in immune cells ( P < 0.001) of the tumor and strong evidence of oligomerization of P2RX7A and B was observed in the HEK expression model, which correlated with a default in the activity of P2RX7. Finally, LUAD patients with a high level of P2RX7B had non-inflamed tumors ( P = 0.001). Conclusion: Our findings identified P2RX7B as a new theranostic tool to restore functional P2RX7 activity and open alternative therapeutic opportunities to improve LUAD patient outcome.

A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

“…Moreover, attempt to facilitate P2RX7 activation in the field of oncology has been limited by the finding that P2RX7 variants expressed by some tumor cells may sustain their proliferation and metabolic activity 2 . To explore this question, we analyzed P2RX7’s functional features in ex vivo lung cancer samples 26 and showed that P2RX7 is functional in leukocytes whereas it is nonfunctional in tumor cells. Considering that P2RX7 is a pro-apoptotic receptor, it makes sense that tumor cells express a nonfunctional receptor.…”

P2X7 Variants in Oncogenesis

“…On the contrary, P2X7B exerts a dominant positive activity at the main isoform [ 8 , 37 ]. The P2X7B variant was probably the most studied, as it is the only one to be functional as a small ion channel [ 8 , 18 , 37 , 38 , 39 , 40 , 41 , 42 ]. The P2X7B isoform retains an intron between exons 10 and 11, causing the addition of 18 extra amino acids after residue 346, which is followed by a stop codon [ 18 ] ( Figure 1 ).…”

“…The P2X7B isoform retains an intron between exons 10 and 11, causing the addition of 18 extra amino acids after residue 346, which is followed by a stop codon [ 18 ] ( Figure 1 ). Nevertheless, P2X7B EC50 is relatively high, and depending upon the cell type and experimental conditions tested, it is not always expressed and functional at the plasma membrane [ 8 , 37 , 41 ]. Another recently identified alternative mRNA for the human P2X7 is P2X7-V3 ( Figure 1 ).…”

“…Finally, the authors suggest that the positive modulation of P2X7A and P2X7B following BzATP treatment might support GSCs invasion, and consequently, P2X7 could be a potential pharmacological target to treat glioblastoma [ 40 ] ( Table 1 ). In 2020, in a study by Benzaquen and colleagues, the P2X7 variants were investigated in lung adenocarcinoma and tumor immune cells [ 41 ]. Interestingly, even though the expression of different P2X7 splice variants was observed in both cancer and immune infiltrate, the authors reported an upregulation of P2X7B, particularly in tumor immune cells.…”

“…They also demonstrated that the expression of P2X7B correlates with the nature of immune infiltration within the tumor. In particular, they found a negative correlation between P2X7B expression and T and B lymphocytes while, on the contrary, there was an increase of myeloid cell content in patients expressing the higher levels of P2X7B [ 41 ] ( Table 1 ). Unfortunately, nothing is known yet about P2X7B role in inflammatory responses classically attributed to P2X7.…”