Soluble Isoform of CD155 Is Elevated in Basal Cell Carcinoma

To the Editor: CD155, also known as the poliovirus receptor or nectin-like protein 5 (Necl-5), a member of the immunoglobulin superfamily (IgSF) nectin-like family,1 plays an essential role in both immunology and oncology; its interaction with TIGIT, CD96, and DNAM-1 inhibits NK and T-cell functions. CD155 is a surface protein expressed on normal and cancerous cells but is overexpressed in most malignancies.2 CD155 mRNA has 4 splicing isoforms: membrane-bound CD155α and CD155δ, as well as soluble proteins sCD155, which consist of CD155γ and CD155β. Research has shown that patients with different types of cancer have elevated levels of CD155 mRNA2 and sCD1553; however, no study has explored sCD155 levels in basal cell carcinoma (BCC). We hypothesized that BCC sCD155 levels are higher compared with healthy controls. Blood samples were collected from 8 patients who consented to participate and met the inclusion criteria, including clinical and histopathological diagnoses of BCC (Figs. 1A, B). Blood samples were obtained from 8 healthy controls with similar demographic characteristics (Fig. 1B). The serum was separated from the collected samples by centrifugation and stored at −20°C. The concentration of sCD155 in the serum was determined using an ELISA assay, following the manufacturer's instructions (Cat. Number EH79RB, Invitrogen, Carlsbad, CA). The Mann–Whitney U test was performed to analyze the statistical differences between the serum concentrations of sCD155 in both groups (Fig. 1D). The results are presented as the standard error of the mean of sCD155 concentration. In addition, individual sCD155 concentrations from each of the 8 patients were also presented (Fig. 1E).FIGURE 1.: A–B, Includes clinical images depicting BCC skin lesions for 8 participants and corresponding histopathological images of the same participants. C, In addition, it presents demographic and clinicopathological data of the participants, followed by sCD155 serum concentrations in patients with BCC and control subjects. D, The statistical analysis was performed using the Mann–Whitney U test (**P < 0.01). Bar charts depict the standard error of the mean of sCD155 concentration, allowing comparison between the BCC group and the control group. E, Individual sCD155 concentrations for the 8 control subjects and 8 patients with BCC are displayed, along with the average concentration of the control group (C Avg).Interestingly, the sCD155 serum concentration we found in patients with BCC was significantly higher than that in healthy controls (P = 0.0011), as shown in Figures 1D and 1E. A recent study by Iguchi et al determined the sCD155 concentration in 262 patients with different cancer types 3. In this study, the median sCD155 concentration (28.3 ng/mL) was lower than in our study (100.3 ng/mL). One possible explanation for the higher BCC sCD155 levels compared with nonskin malignancies described by Iguchi might be explained simply by the differences in antibody affinities or sample sizes used in our methods. We do not discard that these differences in sCD155 levels could be due to the heterogeneity of the cancer types. In addition, BCC is associated with constitutive activation of sonic hedgehog signaling. Sonic hedgehog activation is known to enhance CD155 expression4; consequently, these higher BCC CD155 levels may reflect the intrinsic activation of sonic hedgehog in BCC. CD155 expression levels may not be limited to tumor cells or local immune suppression functions. As a member of the nectins and nectin-like family, higher CD155 expression may respond to the increased demands of cell-to-cell adhesion processes.1 A recent analysis by Malinga et al5 measured four soluble immune checkpoints in BCC. However, their study did not include the quantification of sCD155. Our pilot study is the first to investigate this checkpoint in patients with BCC. The small sample size may have limited the significance of the results. Conducting larger-scale studies in diverse populations is necessary to validate these findings and enhance our understanding of the relationship between sCD155 levels and BCC.