# Circulating ERVFRD-1 and MFSD2A Are Associated with Immunotherapy Response in Metastatic Clear Cell Renal Cell Carcinoma

## TL;DR

This study identifies two genes, ERVFRD-1 and MFSD2A, in blood samples that may predict how well patients with kidney cancer respond to immunotherapy.

## Contribution

The study introduces ERVFRD-1 and MFSD2A as novel blood-based biomarker candidates for predicting immunotherapy response in metastatic clear cell renal cell carcinoma.

## Key findings

- ERVFRD-1 and MFSD2A gene expression was significantly dysregulated in cancer patients compared to healthy controls.
- Patients with progressive disease showed lower ERVFRD-1 and higher MFSD2A expression than those with clinical benefit.
- The genes may serve as non-invasive biomarkers for immunotherapy response, though larger studies are needed.

## Abstract

Immune checkpoint inhibitor (ICI) therapies have improved outcomes for patients with metastatic clear cell renal cell carcinoma (mccRCC). However, many patients do not respond to treatment. Therefore, reliable biomarkers associated with therapeutic response are urgently needed. Blood-based biomarkers offer a non-invasive alternative to tissue analysis. In this study, we investigated the expression of two immunity-related genes, ERVFRD-1 and MFSD2A, in peripheral blood samples from mccRCC patients receiving PD-1-based treatment. Both genes were dysregulated compared with healthy controls and demonstrated differential baseline expression between patients who achieved clinical benefit and those with progressive disease. Patients with progressive disease exhibited decreased expression of ERVFRD-1 and increased expression of MFSD2A. These findings suggest that ERVFRD-1 and MFSD2A may serve as candidate blood-based biomarkers associated with response to ICI, although confirmation in larger prospective studies is required.

Background/Objectives: Immune checkpoint inhibitor (ICI)-based combinations have significantly improved outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, a substantial number of patients fail to derive clinical benefit, highlighting the need for reliable predictive biomarkers. Circulating biomarkers represent an attractive, non-invasive alternative to tissue-based assays. This study aimed to evaluate the immunity-related genes ERVFRD-1 and MFSD2A as potential blood-based candidate biomarkers associated with response to ICI-based therapy in mccRCC. Methods: Peripheral blood samples were collected prior to treatment initiation from 34 patients with mccRCC receiving PD-1-based therapy. Gene expression levels of ERVFRD-1 and MFSD2A were quantified using real-time PCR. Treatment response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Peripheral blood samples from healthy individuals were included as controls. Results: Both ERVFRD-1 and MFSD2A were significantly dysregulated in mccRCC patients compared with healthy controls. Their expression differed between patients with clinical benefit and those with progressive disease. Specifically, patients with progressive disease exhibited reduced ERVFRD-1 expression and increased MFSD2A expression compared with patients showing clinical benefit. Conclusions: ERVFRD-1 and MFSD2A were associated with treatment response in this pilot cohort and may represent promising blood-based biomarker candidates, requiring validation in larger prospective multicenter studies.