Cytotoxic T lymphocyte associated antigen-4 (CTLA4) expression with renal cell carcinoma subtype and staging

  • Muhammad Faham Sangundo 1Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta
  • Indrawarman Soerohardjo Division of Urology, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta
  • Didik Setyo Heriyanto Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada /Dr. Sardjito General Hospital, Yogyakarta, Indonesia
Keywords: renal cell carcinoma;, CLTA-4;, stage;, ; subtype; Indonesia

Abstract

In Indonesia, approximately 45% of renal cell carcinoma (RCC) patients are at an advanced stage that requires checkpoint inhibition combination immunotherapy. Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is associated with poor prognosis of RCC and it is the first checkpoint developed in cancer immunotherapy. This study aimed to investigate CTLA-4 expression among RCC subtypes and staging. Formalin fixed paraffin embedded (FFPE) tissue of RCC patients from 2018-2020 were obtained from the Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta. Expression of CTLA-4 among RCC subtypes and stage was measured using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and compared. Among the 40 patients involved in this study, the CTLA-4 expression was higher in papillary RCC/pRCC (95.88 + 31.58) compared to clear cell RCC/ccRCC (90.94 + 43.05). However, no significantly different in CTL-4 expression based on histologic subtypes and tumor stage (p>0.05). In conclusion, neither the histologic subtype nor the tumor stage of RCC can be predicted by CTLA-4 expression.

References

Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Primers 2017; 3(1):17009.

https://doi.org/10.1038/nrdp.2017.9

Hamid ARAH, Umbas R, Oka AAG, Mochtar CA, Djatisoesanto ahjoe, Soedarso MA, et al. Pedoman Tatalaksana Kanker Ginjal. 2nd ed. IAUI; 2019.

Nabi S, Kessler ER, Bernard B, Flaig TW, Lam ET. Renal cell carcinoma: a review of biology and pathophysiology. F1000Res 2018; 7:307.

https://doi.org/10.12688/f1000research.13179.1

Vasudev NS, Wilson M, Stewart GD, Adeyoju A, Cartledge J, Kimuli M, et al. Challenges of early renal cancer detection: symptom patterns and incidental diagnosis rate in a multicentre prospective UK cohort of patients presenting with suspected renal cancer. BMJ Open 2020; 10(5):e035938.

https://doi.org/10.1136/bmjopen-2019-035938

Harding G, Cella D, Robinson D, Mahadevia PJ, Clark J, Revicki DA. Symptom burden among patients with renal cell carcinoma (RCC): content for a symptom index. Health Qual Life Outcomes 2007; 5:34.

https://doi.org/10.1186/1477-7525-5-34

Padala SA, Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, et al. Epidemiology of renal cell carcinoma. World J Oncol 2020; 11(3):79-7.

https://doi.org/10.14740/wjon1279

Muglia VF, Prando A. Renal cell carcinoma: histological classification and correlation with imaging findings. Radiol Bras 2015; 48(3):166-74.

https://doi.org/10.1590/0100-3984.2013.1927

Cheville JC, Lohse CM, Zinkcke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003; 27(5):612-24.

https://doi.org/10.1097/00000478-200305000-00005

Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000; 163(4):1090-5.

https://doi.org/10.1016/s0022-5347(05)67699-9

Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1):98-106.

https://doi.org/10.1097/COC.0000000000000239

Xiao GF, Yan X, Chen Z, Zhang RJ, Liu TZ, Hu WL. Identification of a novel immune-related prognostic biomarker and small-molecule drugs in clear cell renal cell carcinoma (ccRCC) by a merged microarray-acquired dataset and tcga database. Front Genet 2020; 11:810.

https://doi.org/10.3389/fgene.2020.00810

Kahlmeyer A, Stöhr CG, Hartmann A, Goebell PJ, Wullich B, Wach S, et al. Expression of PD-1 and CTLA-4 are negative prognostic markers in renal cell carcinoma. J Clin Med 2019; 8(5):743.

https://doi.org/10.3390/jcm8050743

Awan MS, Irfan B, Zahid I, Mirza Y, Ali SA. Comparison of polymerase chain reaction and immunohistochemistry assays for analysing human papillomavirus infection in oral squamous cell carcinoma. J Clin Diagn Res 2017; 11(6):XC10-3.

https://doi.org/10.7860/JCDR/2017/24742.10119

Amann R, Fuchs BM. Single-cell identification in microbial communities by improved fluorescence in situ hybridization techniques. Nat Rev Microbiol 2008; 6(5):339-48.

https://doi.org/10.1038/nrmicro1888

Abdulkhaleq F, Larossi N, Ogbonda O, Abu Eid R, Ward F. CTLA-4 expression by human tumor cells and its impact on immunotherapeutic strategies: a systematic review. Immuno-Oncology Insights 2021; 2(3):151-69.

Dursun FSK, Alabalik U. Investigation of pd-l1 (cd274), pd-l2 (pdcd1lg2), and ctla-4 expressions in malignant pleural mesothelioma by immunohistochemistry and real-time polymerase chain reaction methods. Pol J Pathol 2022; 73(2):111-9.

https://doi.org/10.5114/pjp.2022.119752

Liu S, Wang F, Tan W, Zhang L, Dai F, Wang Y, et al. CTLA4 has a profound impact on the landscape of tumor-infiltrating lymphocytes with a high prognosis value in clear cell renal cell carcinoma (ccRCC). Cancer Cell Int 2020; 20(1):519.

https://doi.org/10.1186/s12935-020-01603-2

Lopez-Beltran A, Henriques V, Cimadamore A, Santoni M, Cheng L, Gevaert T, et al. The identification of immunological biomarkers in kidney cancers. Front Oncol 2018; 8:456.

https://doi.org/10.3389/fonc.2018.00456

Tupikowski K, Partyka A, Kolodziej A, Dembowski J, Debinski P, Halon A, et al. CTLA-4 and CD28 genes’ polymorphisms and renal cell carcinoma susceptibility in the Polish population - a prospective study: CTLA-4 and CD28 genes’ polymorphisms and renal cell carcinoma risk. Tissue Antigens 2015; 86(5):353-61.

https://doi.org/10.1111/tan.12671

Grimm MO, Esteban E, Barthélémy P, Schmidinger M, Busch J, Valderrama BP, et al. Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC). J C O 2021; 39(15_suppl):4576.

https://doi.org/10.1200/JCO.2021.39.15_suppl.4576

Park JS, Ham WS, Lee ME, Jang WS, Oh K, Lee N. 34P Addition of oncolytic virus is as effective as addition of cytoreductive nephrectomy to the first-line treatment of anti-PD-1/anti-CTLA-4 antibodies in the murine metastatic renal cell carcinoma model. Annals of Oncology 2022; 33:S557

https://doi.org/10.1016/j.annonc.2022.07.061

Walker LSK, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 2011; 11(12):852-63.

https://doi.org/10.1038/nri3108

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4):252-64.

Xia A, Zhang Y, Xu J, Yin T, Lu XJ. T Cell dysfunction in cancer immunity and immunotherapy. Front Immunol 2019; 10:1719.

https://doi.org/10.3389/fimmu.2019.01719

Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (Anti-CTLA4 Antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007; 30(8):825-30.

https://doi.org/10.1097/CJI.0b013e318156e47e

Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003; 27(5):612-24.

https://doi.org/10.1097/00000478-200305000-00005

Blum KA, Gupta S, Tickoo SK, Chan TA, Russo P, Motzer RJ, et al. Sarcomatoid renal cell carcinoma: biology, natural history and management. Nat Rev Urol 2020; 17(12):659-78.

https://doi.org/10.1038/s41585-020-00382-9

Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A 2008; 105(39):14987-92.

https://doi.org/10.1073/pnas.0806075105.

Klümper N, Ralser DJ, Zarbl R, Schlack K, Schrader AJ, Rehlinghaus M, et al. CTLA4 promoter hypomethylation is a negative prognostic biomarker at initial diagnosis but predicts response and favorable outcome to anti-PD-1 based immunotherapy in clear cell renal cell carcinoma. J Immunother Cancer 2021; 9(8):e002949.

https://doi.org/10.1136/jitc-2021-002949

Huang CH, Han W, Wu YZ, Shen GL. Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma. Front Genet 2022; 13:817656.

https://doi.org/10.3389/fgene.2022.817656

Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 2018; 70:127-37.

https://doi.org/10.1016/j.ctrv.2018.07.009

Wang L, Jiang Z, Qiu H, Tang W, Duan T, Wang L. Associations between CTLA-4 +49 A/G (rs231775) polymorphism and cancer risk: a meta-analysis based on 52 case-control studies. Int J Clin Exp Med 2015; 8(5):6835-51.

Published
2024-06-03
Section
Articles