Introduction: In this study we analyzed major histocompatibility complex class I (MHCI) expression as a potential prognostic immune marker for patients with clear cell renal cell carcinoma (ccRCC). Patients and Methods: 34 patients with localized ccRCC (pT1-pT3) who had undergone nephrectomy and had at least 4 years of clinical follow-up data were included in the study. Immunohistochemical staining for MHCI was performed on tumor sections. An automated image analysis algorithm was applied to representative tumor areas to quantitate the proportion of stained pixels (positivity score = positive pixels/total pixels) on scanned digital slides. Results: At the end of the study, the patients who were alive had increased MHCI expression (mean positivity score 0.80) compared to those who died of the disease (mean positivity score 0.53; p < 0.0001, t test). Patients who were alive with recurrence had increased MHCI expression (positivity score 0.81) compared to those who succumbed to their disease recurrence (positivity score 0.53; p < 0.0001, t test). Survival was higher among patients with high MHCI expression compared to patients with low MHCI expression (p < 0.0001, Mantel-Cox). Conclusions: With an automated high-throughput image analysis technique, this study shows that higher tumor cell MHCI expression promotes increased survival and reduced incidence of recurrence compared to patients with lower tumor cell MHCI expression.

Keywords:
Automated image analysis, Major histocompatibility complex class I, Recurrence, Renal cell carcinoma, Survival
1.
Ramsey S, Lamb GW, Aitchison M, McMillan DC: Prospective study of the relationship between the systemic inflammatory response, prognostic scoring systems and relapse-free and cancer-specific survival in patients undergoing potentially curative resection for renal cancer. BJU Int 2008;101:959-963.
2.
Ljungberg B: Prognostic markers in renal cell carcinoma. Curr Opin Urol 2007;17:303-308.
3.
Osunkoya AO, Grignon DJ: Practical issues and pitfalls in staging tumors of the genitourinary tract. Semin Diagn Pathol 2012;29:154-166.
4.
Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-663.
5.
Qayyum T, McArdle PA, Lamb GW, Going JJ, Orange C, Seywright M, Horgan PG, Oades G, Aitchison MA, Edwards J: Prospective study of the role of inflammation in renal cancer. Urol Int 2012;88:277-281.
6.
Rink M, Chun FK, Robinson B, Sun M, Karakiewicz PI, Bensalah K, Fisch M, Scherr DS, Lee RK, Margulis V, Shariat SF: Tissue-based molecular markers for renal cell carcinoma. Minerva Urol Nefrol 2011;63:293-308.
7.
Vieweg J, Su Z, Dahm P, Kusmartsev S: Reversal of tumor-mediated immunosuppression. Clin Cancer Res 2007;13(2 Pt 2):727s-732s.
8.
Galon J, Pagès F, Marincola FM, Thurin M, Trinchieri G, Fox BA, Gajewski TF, Ascierto PA: The immune score as a new possible approach for the classification of cancer. J Transl Med 2012;10:1.
9.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313:1960-1964.
10.
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;177:1269-1272; discussion 1272.
11.
Frankenberger B, Noessner E, Schendel DJ: Immune suppression in renal cell carcinoma. Semin Cancer Biol 2007;17:330-343.
12.
Pollack BP, Sapkota B, Boss JM: Ultraviolet radiation-induced transcription is associated with gene-specific histone acetylation. Photochem Photobiol 2009;85:652-662.
13.
Pollack BP, Sapkota B, Cartee TV: Epidermal growth factor receptor inhibition augments the expression of MHC class I and II genes. Clin Cancer Res 2011;17:4400-4413.
14.
Brasanac D, Müller CA, Müller GA, Hadzi-Dzokic J, Markovic-Lipkovski J: HLA class I antigens expression in renal cell carcinoma: histopathological and clinical correlation. J Exp Clin Cancer Res 1999;18:505-510.
15.
Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001;19:1649-1657.
16.
Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H: An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002;168:2395-2400.
17.
Galfano A, Novara G, Iafrate M, Cavalleri S, Martignoni G, Gardiman M, D'Elia C, Patard JJ, Artibani W, Ficarra V: Mathematical models for prognostic prediction in patients with renal cell carcinoma. Urol Int 2008;80:113-123.
18.
Krecsák L, Micsik T, Kiszler G, Krenács T, Szabó D, Jónás V, Császár G, Czuni L, Gurzó P, Ficsor L, Molnár B: Technical note on the validation of a semi-automated image analysis software application for estrogen and progesterone receptor detection in breast cancer. Diagn Pathol 2011;6:6.
19.
Sapkota B, Hill CE, Pollack BP: Vemurafenib enhances MHC induction in BRAFV600E homozygous melanoma cells. Oncoimmunology 2013;2:e22890.
20.
Luboldt HJ, Kubens BS, Rübben H, Grosse-Wilde H: Selective loss of human leukocyte antigen class I allele expression in advanced renal cell carcinoma. Cancer Res 1996;56:826-830.
21.
Lindsey KR, Rosenberg SA, Sherry RM: Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2. J Clin Oncol 2000;18:1954-1959.
22.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 2012;366:2443-2454.
23.
Lampen MH, van Hall T: Strategies to counteract MHC-I defects in tumors. Curr Opin Immunol 2011;23:293-298.
24.
Galluzzi L, Senovilla L, Zitvogel L, Kroemer G: The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov 2012;11:215-233.
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2015
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