Tumor Lipids of Pediatric Papillary Renal Cell Carcinoma Stimulate Unconventional T Cells.

Nadine Lehmann,Arthur Wingerter,Alexandra Russo,Nicole Ziegler,Lea Roth,Larissa Seidmann,Roger Sandhoff,Claudia Paret,Nora Backes,Joerg Faber,Khalifa El Malki,Marie Astrid Neu,Sebastian Foersch

doi:10.3389/fimmu.2020.01819

Abstract

Papillary renal cell carcinoma (PRCC) is a rare entity in children with no established therapy protocols for advanced diseases. Immunotherapy is emerging as an important therapeutic tool for childhood cancer. Tumor cells can be recognized and killed by conventional and unconventional T cells. Unconventional T cells are able to recognize lipid antigens presented via CD1 molecules independently from major histocompatibility complex, which offers new alternatives for cancer immunotherapies. The nature of those lipids is largely unknown and α-galactosylceramide is currently used as a synthetic model antigen. In this work, we analyzed infiltrating lymphocytes of two pediatric PRCCs using flow cytometry, immunohistochemistry and qRT-PCR. Moreover, we analyzed the CD1d expression within both tumors. Tumor lipids of PRCC samples and three normal kidney samples were fractionated and the recognition of tumor own lipid fractions by unconventional T cells was analyzed in an in vitro assay. We identified infiltrating lymphocytes including γδ T cells and iNKT cells, as well as CD1d expression in both samples. One lipid fraction, containing ceramides and monoacylglycerides amongst others, was able to induce the proliferation of iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy donors and of one matched PRCC patient. Furthermore, CD1d tetramer stainings revealed that a subset of iNKT cells is able to bind lipids being present in fraction 2 via CD1d. We conclude that PRCCs are infiltrated by conventional and unconventional T cells and express CD1d. Moreover, certain lipids, present in pediatric PRCC, are able to stimulate unconventional T cells. Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs.

Highlights

In contrast to adults, where renal cell carcinoma accounts for two to three percent of all malignancies [1], pediatric renal cell carcinoma is an extremely rare entity
In order to analyze the immunobiology of pediatric Papillary renal cell carcinoma (PRCC), the different T cell subpopulations within the lymphocyte population of two patient samples were quantified by flow cytometry
To further characterize the infiltration of unconventional T cells, it was investigated whether both samples were infiltrated by invariant NKT (iNKT) cells with the specific variant TCR Vα24Jα18 chain. iNKT cells were identified in both samples of pediatric PRCC

Summary

Introduction

In contrast to adults, where renal cell carcinoma accounts for two to three percent of all malignancies [1], pediatric renal cell carcinoma is an extremely rare entity. 1.8–6.3% of all malignant kidney tumors in children are renal cell carcinomas [2, 3] with papillary renal cell carcinoma (PRCC) being the second most common type [4, 5]. Tumor Lipids Stimulate iNKT Cells kidney cell carcinomas in childhood and adolescence from 1980 to 2005 in Germany and from 1989 to 2008 in a hospital in China. Due to the mortality of patients with advanced disease, it is of high interest to characterize the biology of pediatric PRCCs and subsequently provide new options for therapy

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