Aristolochic Acid and Immunotherapy for Urothelial Carcinoma: Directions for unmet Needs

Abstract

Urothelial carcinoma of the bladder (UCB) and upper tracts (UTUC) used to share management with similar principles. However, their genetic and epigenetic differences along with different responses to immunotherapy were recently identified, which are reminiscent of their distinct etiologies. Different from the variety of environmental factors relating to UCB, UTUC is best known for its close relationship with exposure to aristolochic acid (AA). AA is believed to cause its carcinogenicity through forming DNA adducts of deoxyadenosine-aristolactam, as well as A:T → T:A transversions in the TP53 tumor suppressor gene. Since recent findings suggested that cancers with higher somatic mutations are associated with better treatment responses upon immune checkpoint blockade, UTUC and AA-related biomarkers reasonably serve as good candidates, as well as a potential prognostic predictor for the flourishing immunotherapy. This review covers the current state of the literature on the clinical response of UTUC and UCB receiving immunotherapy and points out directions for refinement regarding patient selection.

Keywords: aristolochic acid; immune checkpoint inhibitors; mutation load; upper tract urothelial carcinoma; urothelial carcinoma of the bladder.

Figure 1

An example of AA-derived DNA adducts leading to gene mutations. After reductive metabolism, AA-derived DNA adducts are bound to the exocyclic amino groups of purine bases through their electrophilic cyclic N-acylnitrenium ion. If the adducts persisted through DNA replications, mutations, such as an A:T → T:A transversion in TP53 gene, may occur.