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Differences in the frequencies of HLA-class I and II alleles between German patients with renal cell carcinoma and healthy controls: Beyond the Abstract

Renal cell carcinoma (RCC) is the ninth most frequent cancer worldwide, and there were approximately 338,000 new cases diagnosed in 2012.[1] Tumors of RCC are unusual among solid tumors as they are considered to be immunogenic tumors that are sensitive to immune attack.[2,3] The human leukocyte antigen (HLA) system is a major part of the human immune system and has an impact on tumor initiation, tumor progression and immunosurveillance. Several studies have shown that the occurrence of different HLA alleles may have either a predisposing effect for RCC or a protective effect against RCC.

We studied the allele frequencies of four gene loci (HLA-class I: HLA-A, -B, -C and HLA-class II: HLA-DR) in a cohort of German renal cell carcinoma (RCC) patients and in healthy controls. The occurrence of the HLA-C*12 allele was significantly increased in German RCC patients compared with healthy controls (P < 0.005; Fisher’s exact test), whereas the occurrence of the HLA-DRB1*04 allele was significantly reduced in RCC patients compared with healthy controls (P < 0.05; Fisher’s exact test). However, the presence of allele HLA-C*12 was only somewhat but not significantly associated with 10 years overall survival.  

Why do we think that the determination of the frequency of HLA alleles could be important? 

There are reports in the literature that show that patients with HLA class I-positive RCC (detected by immunohistochemical staining) showed longer recurrence-free survival than those with down-regulated expression.[4] Accordingly, in clear cell RCC, the down-regulation of HLA class I expression is associated with tumor progression and poor prognosis.[5] But beyond these prognostic correlations, HLA alleles may have also a predictive impact on therapy response including immunotherapies. In this way HLA alleles may affect therapies negatively or support them. It is known that HLA-DRB1*04 alleles might promote binding and presentation of an immunogenic peptide, however, this may facilitate (a not desired) antibody development to IFN-b treatment as suggested for multiple sclerosis patients.[6] However, recently, it was shown that the expression of the programmed death-ligand 1 (PD-L1) - suggested to play a major role in suppressing the immune system – significantly, positively correlated with other immune parameters such as a high number of tumor-infiltrating lymphocytes and expression of HLA class I antigens in chondrosarcoma.[7] In addition, PD-L1-derived peptides were capable of inducing cancer-reactive cytotoxic T lymphocytes in HLA-A24+ Patients with RCC.[8] It would be of high interest to study the relationship between the response to targeted and/or immunotherapy and the presence of different HLA alleles (different impact of HLA-class I and HLA-class II alleles or in-between each class?) in RCC patients.

Altogether, we suggest that the presence of HLA alleles can affect development of RCC and could add knowledge as predictive marker for future targeted/immunotherapies.

Written By: Helge Taubert, Ph.D., Urologische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91052 Erlangen, Germany;  Steffen Goebel, Ph.D., Institute of Transfusion Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany

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References: 
  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 136(5):E359-386. doi: 10.1002/ijc.29210.
  2. Finke JH, Rayman P, Alexander J, Edinger M, Tubbs RR, Connelly R, Pontes E, Bukowski R. Characterization of the cytolytic activity of CD4+ and CD8+ tumorinfiltrating lymphocytes in human renal cell carcinoma. Cancer Res. 1990;50(8):2363-2370.
  3. Yang JC, Childs R. Immunotherapy for renal cell cancer. J Clin Oncol. 2006;24(35):5576–83.
  4. Kitamura H, Honma I, Torigoe T, Asanuma H, Sato N, Tsukamoto T. Down-regulation of HLA class I antigen is an independent prognostic factor for clear cell renal cell carcinoma. J Urol. 2007;177(4):1269-1272.
  5. Yuan J, Liu S, Yu Q, Lin Y, Bi Y, Wang Y, An R. Down-regulation of human leukocyte antigen class I (HLA-I) is associated with poor prognosis in patients with clear cell renal cell carcinoma. Acta Histochem 2013;115(5):470-474. doi: 10.1016/j.acthis.2012.11.002.
  6. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermüller J, Stadler PF, Hartung HP, Berthele A, Deisenhammer F, Wassmuth R, Hemmer B. HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet. 2008;83(2):219-227.
  7. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovée JV () Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol. 2016; 29(9):1028-1037. doi: 10.1038/modpathol.2016.108.
  8. Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco M, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H. Identification of Programmed Death Ligand 1-derived Peptides Capable of Inducing Cancer-reactive Cytotoxic T Lymphocytes From HLA-A24+ Patients With Renal Cell Carcinoma. J Immunother. 2015;38(7):285-291.