Abstract
Metastatic urothelial carcinoma (mUC) has a very high mutational rate and is associated with an APOBEC mutation signature. We examined the correlation of APOBEC expression with overall survival (OS) and PD-L1 expression in a cohort of 73 mUC patients. mRNA expression of APOBEC3 family of genes (A3A, A3B, A3C, A3F_a, A3F_b, A3G, A3H) was measured using Nanostring. PD-L1 expression, evaluated by immunohistochemistry, on tumor infiltrating mononuclear cells (TIMCs) and tumor cells was scored from 0 to 4, with 2–4 being positive. Wilcoxon’s non-parametric tests assessed the association of APOBEC and PD-L1. The Cox regression model assessed the association of APOBEC with OS. All APOBEC genes were expressed in mUC. Increased A3A, A3D, and A3H expression associates with PD-L1 positive TIMCs (p = 0.0009, 0.009, 0.06). Decreased A3B expression was marginally associated with PD-L1 positive TIMCs expression (p = 0.05). Increased A3F_a and A3F_b expression was associated with increased expression of PD-L1 on tumor cells (p = 0.05). Increased expression of A3D and A3H was associated with longer OS (p = 0.0009). Specific APOBEC genes have different effects on mUC in terms of survival and PD-L1 expression. A3D and A3H may have the most important role in mUC as they are associated with OS and PD-L1 TIMC expression.
Highlights
In the United States, there were more than 76,000 cases and more than 16,000 deaths from urothelial carcinoma (UC) in 20141
PD-L1 tumor cell and PD-L1 MNC expression across the entire cohort is described in Table 2. mRNA expression level of APOBEC3A (A3A), APOBEC3B (A3B), APOBEC3C (A3C), APOBEC3D (A3D), APOBEC3F_a (A3F_a), APOBEC3F_b (A3F_b), APOBEC3G (A3G), and APOBEC3H (A3H) were measured using Nanostring and expression levels were dichotomized at the median
We initially explored the correlation between APOBEC expression and overall survival (OS), as increased mutations correlate with response to platinum in UC18 (Table 4)
Summary
In the United States, there were more than 76,000 cases and more than 16,000 deaths from urothelial carcinoma (UC) in 20141. Urothelial cancer has one of the highest mutational rates of all cancers, mean of 7.7 mutations per megabase[7,9]. It has been demonstrated that increased number of mutations correlate with better response rates to chemotherapy[18]. Since the anti-tumor immune response targets neoantigens, a higher neoantigen load means more reactive T cells and IFN-g production[19]. As a tumor evolves to evade the immune response, this IFN-g production may increase PD-L1 expression on tumor cells and TIMC, strengthening immune evasion. This could help to explain response to immunotherapy and will deserve further exploration in immunotherapy treated patients in future trials
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
