Major histocompatibility complex class I (MHC 1) expression in clear cell renal cell carcinoma: Correlation with clinical outcome.

541 Background: Most patients with clear cell renal cell carcinoma (ccRCC) initially present with localized disease but a fraction subsequently develop metastases. Current predictive models of ccRCC recurrence are imperfect, suggesting a need for additional predictors. Metastatic ccRCC may be modulated by the immune system, suggesting that the immune system plays a role in tumor progression. Major histocompatibility complex class I (MHC I) expression on tumor cells is critical for immune system recognition. Here, we analyzed MHC I expression in ccRCC and its correlation with clinical outcomes. Methods: ccRCC patients who underwent radical nephrectomy with a ≥4 years of follow-up, without T4 disease or metastasis at presentation were included. All slides were re-reviewed by a single Urologic Pathologist and blocks with tumor and adjacent renal parenchyma were selected for each case for immunohistochemical staining for MHC I . Whole slide scanning and automated image analysis was used; representative areas of tumor and normal kidney were selected and averaged with Aperio image analysis software (positive pixel count v. 9). Unpaired t-test and one-way ANOVA were performed in GraphPad Prism. Results: 34 patients were analyzed. Fuhrman nuclear grades (FNG) were: FNG 2 10/34 (29%), FNG 3 20/34 (59%) and FNG 4 4/34 (11%). Although there was no correlation with FNG and MHC1 (ANOVA, p=0.800), patients who were alive at follow up had increased MHCI expression (80.1% average positivity score) than those who died (53% average positivity score; t-test, p<0.0001). Patients living with recurrence had increased MHCI expression (81.3% positivity score) compared to those who succumbed to their disease (53.2% positivity score; t-test, p<0.0001). Conclusions: MHCI expression may be an important prognostic factor in ccRCC for recurrence free survival, and also for prognosis of those patients with recurrence. This is the first study to show that increased MHCI expression is a favorable prognostic indicator in metastatic ccRCC. These results suggest that MHCI expression plays an important role in tumor-host immune system interaction of ccRCC and merits further study.

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Evaluation of major histocompatibility complex class I expression in clear cell renal cell carcinoma as a prognostic tool.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.469 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 469-469

Author(s):

Claire M. de la Calle ◽

Sarah A. Holzman ◽

Umer Sheikh ◽

Jonathan H. Huang ◽

Haydn T. Kissick ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Image Analysis ◽

Major Histocompatibility Complex ◽

Clear Cell ◽

T Test ◽

Complex Class ◽

Cell Renal Cell Carcinoma ◽

Histocompatibility Complex ◽

Tumor Expression

469 Background: After nephrectomy for clear cell renal cell carcinoma (ccRCC) approximately one-third of patients develop metastases. Yet, with currently used prognostic tools such as the TNM staging and the Fuhrman nuclear grade (FNG) system, it is difficult to accurately assess prognosis for each patient. Here, we evaluated Major Histocompatibility Complex Class I (MHCI) expression as a potential prognostic immune marker in ccRCC. Methods: Fifty-five post-nephrectomy patients that presented with localized ccRCC were included. All patients had four or more years of follow up. MHCI was stained in the tumor sections via immunohistochemistry. Then, via an automated image analysis algorithm MHCI expression was quantitated with the Positivity score, the ratio of positively stained pixels over the total number of pixels. Results: Mean MHCI positivity score of the cohort was 0.75 (SE= ±0.20). At the end of the follow-up period, the patients who were alive had higher MHCI expression (0.80 positivity score; SE ±0.14) than those who died of disease (0.62 positivity score; SE= ±0.16; t test, p<0.0001). MHCI positivity scores above the mean were associated with increased cancer specific survival (Mantel-Cox, p=0.0021). MHCI expression was higher among patients with no recurrence (0.80; SE= ±0.16) compared to those that recurred during the study period (0.70; SE= ±0.22; t test, p=0.017); and time-to-recurrence was longer in patients with above mean MHCI positivity scores (Mantel-Cox, p=0.017). Patients who were alive with recurrence had increased MHCI expression (0.81; SE= ±0.10) compared to those who succumbed to disease recurrence (0.62; SE= ±0.25; t-test, p=0.0009). No correlation was detected between FNG and tumor expression of MHCI (ANOVA, p=0.655, F=0.423) or between stage at presentation and MHCI tumor expression (ANOVA, p=0.734, F=0.311). Conclusions: With an automated high-throughput image analysis, this cohort shows that increased MHCI expression in ccRCC is associated with improved prognosis after curative nephrectomy.

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High Expression of Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma Is Associated with Improved Prognosis

Urologia Internationalis ◽

10.1159/000370164 ◽

2015 ◽

Vol 95 (1) ◽

pp. 72-78 ◽

Cited By ~ 2

Author(s):

Sarah A. Holzman ◽

Claire M. de la Calle ◽

Haydn T. Kissick ◽

Adeboye O. Osunkoya ◽

Brian P. Pollack ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Image Analysis ◽

Major Histocompatibility Complex ◽

Tumor Cell ◽

Major Histocompatibility Complex Class ◽

Renal Cell ◽

Clear Cell ◽

Complex Class ◽

Cell Renal Cell Carcinoma ◽

Histocompatibility Complex

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.

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MP36-03 MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I EXPRESSION IN CLEAR CELL RENAL CELL CARCINOMA: CORRELATION WITH CLINICAL OUTCOME

The Journal of Urology ◽

10.1016/j.juro.2014.02.1067 ◽

2014 ◽

Vol 191 (4S) ◽

Author(s):

Sarah Holzman ◽

Adeboye Osunkoya ◽

Brian Pollack ◽

Kenneth Ogan ◽

Viraj Master

Keyword(s):

Renal Cell Carcinoma ◽

Major Histocompatibility Complex ◽

Clinical Outcome ◽

Major Histocompatibility Complex Class ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Complex Class ◽

Cell Renal Cell Carcinoma ◽

Histocompatibility Complex

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Implications of Programmed Death Ligand-1 Positivity in Non-Clear Cell Renal Cell Carcinoma

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2018.107 ◽

2018 ◽

Vol 5 (4) ◽

pp. 6-13 ◽

Cited By ~ 2

Author(s):

Juan Chipollini ◽

Mounsif Azizi ◽

Charles C Peyton ◽

Dominic H Tang ◽

Jasreman Dhillon ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Type I ◽

Cell Renal Cell Carcinoma ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Papillary Type

The purpose of this study was to assess the prognostic value of programmed death ligand-1 (PD-L1) positivity in a non-clear cell renal cell carcinoma (non-ccRCC) cohort. PD-L1 expression was evaluated by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) specimens from 45 non-ccRCC patients with available tissue. PD-L1 positivity was defined as ?1% of staining. Histopathological characteristics and oncological outcomes were correlated to PD-L1 expression. Cancer-specific survival (CSS) and recurrence-free survival (RFS) stratified by PD-L1 status were estimated using the Kaplan–Meier method. Median age was 58 years and median follow-up was 40 months. Non-ccRCC subtypes included sarcomatoid (n = 9), rhabdoid (n = 6), medullary (n = 2), Xp11.2 translocation (n = 2), collecting duct (n = 1), papillary type I (n = 11), and papillary type II (n = 14). PD-L1 positivity was noted in nine (20%) patients. PD-L1 positivity was significantly associated with higher Fuhrman nuclear grade (P = 0.048) and perineural invasion (P = 0.043). Five-year CSS was 73.2 and 83% for PD-L1 positive and negative tumors, respectively (P = 0.47). Five-year RFS was 55.6 and 61.5% for PD-L1 positive and negative tumors, respectively (P = 0.58). PD-L1 was expressed in a fifth of non-ccRCC cases and was associated with adverse histopathologic features. Expression of biomarkers such PD-L1 may help better risk-stratify non-ccRCC patients to guide treatment decisions and follow-up strategies.

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Transmembrane Helices Are an Over-Presented and Evolutionarily Conserved Source of Major Histocompatibility Complex Class I and II Epitopes

Frontiers in Immunology ◽

10.3389/fimmu.2021.763044 ◽

2022 ◽

Vol 12 ◽

Author(s):

Richèl J. C. Bilderbeek ◽

Maksim V. Baranov ◽

Geert van den Bogaart ◽

Frans Bianchi

Keyword(s):

T Cell ◽

Membrane Proteins ◽

T Cell Responses ◽

Class I ◽

Complex Class ◽

Transmembrane Helices ◽

Class I Mhc ◽

Mhc I ◽

Cell Responses ◽

Histocompatibility Complex

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.

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Transmembrane helices are an overlooked and evolutionarily conserved source of major histocompatibility complex class II epitopes

10.1101/2021.05.02.441235 ◽

2021 ◽

Author(s):

Richel Bilderbeek ◽

Maksim Baranov ◽

Frans Bianchi ◽

Geert van den Bogaart

Keyword(s):

T Cell ◽

Membrane Proteins ◽

T Cell Responses ◽

Nucleotide Polymorphisms ◽

Complex Class ◽

Transmembrane Helices ◽

Class I Mhc ◽

Mhc I ◽

Cell Responses ◽

Histocompatibility Complex

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most haplotypes of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefor peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells respond more to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs therefor are less prone to escape mutations that enable pathogens to evade T cell responses.

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