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Annals of Surgical Oncology 9:587-593 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Presence of the Human Leukocyte Antigen Class II Gene DRB1*1101 Predicts Interferon {gamma} Levels and Disease Recurrence in Melanoma Patients

Jeffrey E. Lee, MD, Joseph Abdalla, MS, Geoffrey A. Porter, MD, Loretta Bradford, Elizabeth A. Grimm, PhD, John D. Reveille, MD, Paul F. Mansfield, MD, Jeffrey E. Gershenwald, MD and Merrick I. Ross, MD

From the Department of Surgical Oncology (JEL, JA, GAP, LB, PFM, JEG, MIR) and the Department of Bioimmunotherapy (EAG), The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and the Division of Molecular Rheumatology and Immunology (JDR), The University of Texas Health Science Center at Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Jeffrey E. Lee, MD, Department of Surgical Oncology, Box 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-745-4426; E-mail: jelee{at}notes.mdacc.tmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Increased interferon {gamma} (IFN-{gamma}) levels are an independent predictor of melanoma recurrence. Human leukocyte antigen (HLA) class II genes can regulate cytokine production; we investigated whether these genes would predict IFN-{gamma} levels and recurrence in melanoma patients.

Methods: Of 591 patients who presented with localized melanoma, 579 underwent identification of HLA class II alleles; 233 melanoma patients and 90 controls underwent determination of plasma IFN-{gamma} levels. HLA class II genes were examined for association with IFN-{gamma} levels and disease recurrence.

Results: After a median follow-up of 60 months, melanoma patients with IFN-{gamma} levels above the mean control value were more likely to have developed disease recurrence compared with patients with levels below the mean. The HLA class II gene HLA-DRB1*1101 was the strongest predictor of recurrence, and HLA-DRB1*1101-positive melanoma patients had increased levels of IFN-{gamma} compared with patients lacking the gene.

Conclusions: Among patients with localized melanoma, both HLA-DRB1*1101 and increased IFN-{gamma} levels were associated with an increased risk for recurrence; HLA-DRB1*1101-positive patients had relatively increased levels of IFN-{gamma}. HLA class II genes may mediate cytokine production in melanoma patients, and this mechanism may help determine the risk of disease recurrence.

Key Words: Melanoma • Interferon {gamma} • HLA class II • Disease recurrence


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Most patients presenting with localized melanoma will be cured with surgery alone. The prognosis for patients with histologically negative sentinel lymph nodes is particularly good.1 However, there exists a subpopulation of patients presenting with localized melanoma whose disease recurs despite the overall good prognosis of the group. Identification of predictors of recurrence in this otherwise low-risk population may help identify mechanisms responsible for melanoma progression, identify a population of melanoma patients at higher risk for disease recurrence who may benefit from adjuvant therapies, and suggest potential novel therapeutic approaches for high-risk melanoma patients.

Human leukocyte antigen (HLA) class I or class II molecules on the surfaces of melanoma cells bind tumor antigen–derived peptides, resulting in T cell–mediated target cytolysis or cytokine production. T-cell recognition of the HLA class II molecule/tumor peptide complex can either induce an effective antimelanoma immune response2 or impair that immune response (antigen-specific immune nonresponsiveness, or anergy).3 Specific HLA class II alleles (forms of the gene) have been found at increased frequency in patients with certain cancers, including patients with cervical carcinoma,4 human T-lymphotrophic virus 1–associated leukemia/lymphoma,5 and gastric cancer.6 Our prior studies have revealed a strong association between the HLA class II gene HLA-DQB1*0301 and advanced-stage melanoma,7,8 and we have identified HLA-DQB1*0301 as an independent predictor of disease recurrence in melanoma patients presenting with localized disease.9 These results indicate that HLA class II alleles are promising molecular prognostic markers in melanoma patients.

Increased levels of various cytokines have been implicated in certain advanced-stage or recurrent solid tumors.10–12 We recently hypothesized that increased levels of certain cytokines might help explain the unexpected recurrences observed in melanoma patients who, by standard objective criteria, seemed to be at low risk for disease recurrence. We therefore investigated whether levels of interleukin-2 (IL-4), IL-6, IL-10, tumor necrosis factor {alpha}, or interferon {gamma} (IFN-{gamma}) would predict disease recurrence in melanoma patients with histologically negative sentinel lymph nodes. In this study,13 218 patients with early-stage melanoma and histologically negative sentinel lymph nodes had significantly higher levels of IL-4, IL-6, and IL-10 than did 90 controls without cancer, and the overall levels of IFN-{gamma} in the melanoma patients were relatively suppressed. It is interesting to note that high IFN-{gamma} levels were independently associated with an increased risk of melanoma recurrence. This was the first study to identify altered cytokine levels in early-stage melanoma patients and to correlate those levels with risk of disease recurrence. The results suggest that altered levels of specific plasma cytokines, especially IFN-{gamma}, are promising prognostic markers in melanoma patients. Because HLA class II alleles can regulate cytokine production14 and because specific HLA class II alleles are independent predictors of melanoma recurrence,9 we investigated whether HLA class II alleles would predict IFN-{gamma} levels and disease recurrence in melanoma patients presenting with localized disease.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Controls
Approval for this research project was obtained from both the Surveillance Committee for Human Subjects Research and the Office of the Vice President for Research at The University of Texas M. D. Anderson Cancer Center. Informed consent was obtained from all patients. Melanoma patients presenting with clinically localized disease evaluated in the Melanoma Surgery Clinic at M. D. Anderson Cancer Center between July 1991 and September 1999 were considered for inclusion. A prospective database was created.9 American Joint Committee on Cancer (AJCC) stage at presentation was determined by direct physical examination and pathologic review, supplemented by laboratory and radiographical examinations.1,9 Patients with localized melanoma received standard definitive surgical therapy for primary melanoma. Elective lymph node dissection or intraoperative lymphatic mapping, sentinel node biopsy, and selective lymphadenectomy were performed at the discretion of the operating surgeon and in consultation with the individual patient, following standard criteria developed in the Section of Melanoma Surgery.1,15 Patients with localized (AJCC stage I and II) melanoma received only surgical therapy. The primary clinical outcome in this study was recurrence, expressed as disease-free survival. Recurrence was identified by prospective follow-up; follow-up of melanoma patients was standardized by stage of disease. Volunteer control individuals without cancer had blood drawn for determination of IFN-{gamma} levels.

Cytokine Levels
Plasma cytokine levels of IFN-{gamma} were determined by using an immunosorbent assay (CytoscreenTM; Biosource International, Inc., Camarillo, CA).13 All measurements were performed according to the procedures recommended by the manufacturer. Plasma samples from melanoma patients were obtained before wide local excision and sentinel lymph node biopsy. Samples were stored frozen at -80°C before analysis, and plasma IFN-{gamma} levels were batch-processed from thawed samples. Results of IFN-{gamma} testing were analyzed and recorded in a blinded fashion, independent of HLA class II typing and clinical data acquisition.

HLA Class II Molecular Oligotyping
DNA was extracted from peripheral blood samples with phenol-chloroform-isoamyl alcohol. The patients’ DNA served as the substrate for polymerase chain reaction (PCR)/sequence-specific oligonucleotides HLA class II typing. PCR amplification of locus-specific fragments of the HLA class II gene was performed.6–9,16 Because there are many HLA-DRB1 alleles that have similar sequences, HLA-DRB1 typing was performed in a stepwise manner. The sizes of the PCR products were analyzed by electrophoresis. The amplified DNA was blotted to HybondTM N+ membranes (Amersham, Arlington Heights, IL), and the blotted membranes were hybridized with [{gamma}32P]adenosine triphosphate–labeled sequence-specific oligonucleotides probes. Results of HLA class II typing were analyzed and recorded in a blinded fashion, independent of IFN-{gamma} levels and clinical data acquisition.

Statistical Analysis
Standard melanoma prognostic factors were examined for association with disease recurrence and for association with IFN-{gamma} levels and HLA class II type. IFN-{gamma} levels were examined for association with disease recurrence. Common HLA class II genes identified in at least 5% of this melanoma population were examined for association with disease recurrence and IFN-{gamma} levels. Univariate analyses included the {chi}2 test to compare categorical variables and Student’s t-test to compare continuous data. Kaplan-Meier survival curves were constructed by using melanoma recurrence as the end point. The log-rank test was used to test for statistical significance between Kaplan-Meier curves. Two-tailed tests were used wherever the data so allowed, and statistical significance was set a priori at P < .05. Potential prognostic factors identified as significant at the P < .05 level on univariate analysis were subjected to multivariate analysis with Cox proportional hazards regression model. All analyses were performed with Statistica 5.5 for WindowsTM (StatSoft, Tulsa, OK).9,13


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study and Patient Characteristics
Five hundred ninety-one melanoma patients who presented with localized melanoma (AJCC stage I or II) were entered into a prospective melanoma database. HLA class II alleles were determined in 579 patients. Preoperative plasma samples were available from 233 melanoma patients; these samples underwent testing for determination of pretreatment plasma IFN-{gamma} levels. Two hundred twenty patients who had IFN-{gamma} levels determined also had HLA class II typing performed. IFN-{gamma} levels were also determined in 90 control individuals without cancer. There was no significant age distribution difference between melanoma patients and controls; furthermore, we did not detect a significant association between age and IFN-{gamma} levels in either the melanoma or the control group (data not shown). Three hundred twenty-five melanoma patients (55.0%) underwent wide local excision alone. Wide local excision was combined with sentinel lymph node biopsy in 228 patients (38.6%), with elective lymph node dissection in 26 patients (4.4%) and with both sentinel lymph node biopsy and completion elective lymph node dissection in 12 patients (2.0%). Clinical and pathologic characteristics of the total cohort of patients are listed in Table 1. There were no significant differences in these clinical and pathologic characteristics between the subsets of melanoma patients who underwent HLA typing and those who underwent determination of plasma IFN-{gamma} levels (data not shown). The median follow-up in the study cohort was 60 months. A total of 178 patients (30.1%) had melanoma recurrence, 116 patients (65.2%) had recurrence with distant metastases, 55 patients (30.9%) had regional recurrence, and 7 (3.9%) had local recurrence.


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  		TABLE 1. TABLE 1. Clinical and pathologic characteristics of the study cohort (n = 591)
 
IFN-{gamma} Levels and Melanoma Recurrence
The mean IFN-{gamma} level in the 233 melanoma patients was 4.60 pg/mL (range, 0–121 pg/mL), whereas the mean IFN-{gamma} level in the 90 controls was 7.80 pg/mL (range, 0–121 pg/mL; P = .046 by Student’s t-test). Fifty-five of 233 (23.6%) melanoma patients had detectable levels of IFN-{gamma}, whereas 34 of 90 controls (37.8%) had detectable levels of IFN-{gamma} (P = .011 by {chi}2 test). Melanoma patients with IFN-{gamma} levels above the mean control value of 7.8 pg/mL were more likely to develop disease recurrence compared with patients with levels below the mean (Fig. 1; 5-year disease-free survival, 61% vs. 84%; P = .032). Reanalysis of melanoma recurrence rates by using alternative methods of dichotomizing the patients by IFN-{gamma} levels (detectable vs. undetectable, mean of the melanoma patient population), as well as a regression analysis treating the IFN-{gamma} level as a continuous variable, resulted in slightly different P values but did not alter the statistical significance of the association (data not shown). There was no difference with regard to standard melanoma clinicopathologic factors (sex, age, primary tumor thickness, Clark level of invasion, presence of ulceration, or anatomical location of the primary site) between melanoma patients with relatively high or low IFN-{gamma} levels (data not shown).



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  		FIG. 1. Disease-free survival rate for 233 American Joint Committee on Cancer stage I or II melanoma patients by interferon {gamma} (IFN-{gamma}) status. Patients were divided into those with relatively high and low IFN-{gamma} levels according to the mean IFN-{gamma} level in the control population (7.8 pg/mL). The median follow-up was 60 months, and the minimum follow-up was 6 months. The overall 5-year disease-free survival rate was 80%. The 5-year disease-free survival rate of the high–IFN-{gamma} patients was 61%; the 5-year disease-free survival rate of the low–IFN-{gamma} patients was 84% (log-rank, P = .032).

 
HLA Class II Alleles and Melanoma Recurrence
HLA class II alleles representing at least 5% of the study population were investigated for association with melanoma recurrence (Table 2). Alleles investigated included eight HLA-DRB1 alleles, seven HLA-DQB1 alleles, and six HLA-DQA1 alleles. A single HLA-DRB1 allele, HLA-DRB1*1101, was associated with an increased risk of melanoma recurrence (Fig. 2; 5-year disease-free survival, HLA-DRB1*1101–positive vs. –negative, 53% vs. 70%; P = .007). Likewise, a single HLA-DQB1 allele, HLA-DQB1*0301, was associated with an increased risk of melanoma recurrence (Fig. 3; 5-year disease-free survival, HLA-DQB1*0301–positive vs. –negative, 66% vs. 74%; P = .022). Although there was a trend associating the HLA-DQA1 allele HLA-DQA1*0302 with melanoma recurrence, this observation did not reach statistical significance (P = .07). None of the alleles investigated was associated with alterations in standard melanoma clinicopathologic factors (sex, age, primary tumor thickness, Clark level of invasion, presence of ulceration, or anatomical location of the primary site; data not shown).


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  		TABLE 2. TABLE 2. Association of HLA class II alleles with melanoma recurrence in 579 stage I or II melanoma patients
 


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  		FIG. 2. Disease-free survival rate for 579 American Joint Committee on Cancer stage I or II melanoma patients by HLA-DRB1*1101 status. The median follow-up was 60 months, and the minimum follow-up was 6 months. The overall 5-year disease-free survival rate was 69%. The 5-year disease-free survival rate of the HLA-DRB1*1101–positive patients was 53%; the 5-year disease-free survival rate of the HLA-DRB1*1101–negative patients was 70% (log-rank, P = .007).

 


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  		FIG. 3. Disease-free survival rate for 579 American Joint Committee on Cancer stage I or II melanoma patients by HLA-DQB1*0301 status. The median follow-up was 60 months, and the minimum follow-up was 6 months. The overall 5-year disease-free survival rate was 69%. The 5-year disease-free survival rate of the HLA-DQB1*0301–positive patients was 66%; the 5-year disease-free survival rate of the HLA-DQB1*0301–negative patients was 74% (log-rank, P = .022).

 
Multivariate Analysis of Melanoma Prognostic Indicators
The standard melanoma prognostic indicators, consisting of primary tumor thickness, Clark level of invasion, and presence of ulceration, were strongly associated with melanoma recurrence on both univariate and multivariate analysis (Table 3). HLA-DRB1*1101 status and IFN-{gamma} level (dichotomized by the mean IFN-{gamma} level in the control population) retained their association with melanoma recurrence on multivariate analysis. HLA-DQB1*0301 status, however, although it was associated with melanoma recurrence on univariate analysis, was not an independent predictor of recurrence in a model that included HLA-DRB1*1101 status. Because HLA-DQB1*0301 and HLA-DRB1*1101 are known to be strongly genetically linked to each other, and because these two alleles were strongly associated with each other in this melanoma patient population ({chi}2; P < .00001), we performed a repeat Cox analysis after excluding HLA-DRB1*1101 status. In this reanalysis, HLA-DQB1*0301 retained its independent prognostic value (P = .003).


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  		TABLE 3. TABLE 3. Summary of prognostic indicators for disease-free survival in 591 AJCC stage I or II melanoma patients
 
Analysis of IFN-{gamma} Levels by HLA Class II Status
Results of the analysis of IFN-{gamma} levels by HLA class II status in 220 melanoma patients who underwent determination of both IFN-{gamma} levels and HLA class II alleles are listed in Table 4. A single HLA class II allele, HLA-DRB1*1101, was associated with a relatively increased level of IFN-{gamma}. No other HLA class II allele was associated with an altered level of IFN-{gamma}.


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  		TABLE 4. TABLE 4. IFN-{gamma} level by HLA class II status in 220 melanoma patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, patients with early-stage melanoma who had clinically localized disease and were treated with surgery alone had relatively suppressed levels of IFN-{gamma} compared with noncancer controls. In contrast, high IFN-{gamma} levels were independently associated with an increased risk of melanoma progression. These results are similar to those seen and recently reported in the subset of these patients who underwent sentinel node identification.13

In this study we also identified a set of two HLA class II alleles, HLA-DRB1*1101 and HLA-DQB1*0301, which were associated with melanoma recurrence. HLA-DRB*1101 and HLA-DQB1*0301 were strongly genetically linked to each other in this patient population, and they are a lso in linkage disequilibrium in the white population in general. In this study, the less common HLA-DRB1*1101 allele (14.7% of patients) was more strongly associated with melanoma recurrence than the more common HLA-DQB1*0301 allele (38.6% of patients). Furthermore, HLA-DQB1*0301 was an independent predictor of melanoma recurrence only when HLA-DRB1*1101 was excluded from the multivariate analysis. Although independent contributions from these two alleles are not excluded by these results, they do suggest that our previously reported association between HLA-DQB1*0301 and melanoma recurrence7–9 may be due to its strong genetic linkage with the HLA-DRB1*1101 allele.

Finally, our results demonstrate an association between a single HLA class II allele, again HLA-DRB1*1101, and relatively increased levels of IFN-{gamma}. These results taken together suggest that HLA class II genes could help regulate IFN-{gamma} levels in melanoma patients14 and that this mechanism could help determine the risk of melanoma recurrence. It is important to recognize, however, that the independent statistical associations observed for IFN-{gamma} levels and HLA-DRB1*1101 in association with melanoma recurrence (Table 3) suggest that additional mechanisms are also likely to be involved.

Potential mechanisms that could be responsible for the presence of increased levels of IFN-{gamma} in melanoma patients who have recurrence include (1) the production of IFN-{gamma} by occult melanoma metastases, (2) the production of IFN-{gamma} by lymphocytes in response to the antigenic challenge of the tumor, or (3) genetic regulation of IFN-{gamma} production. Direct evidence regarding these mechanisms will require additional investigations. However, with regard to the first mechanism, although melanoma tumors commonly produce a variety of cytokines, production of IFN-{gamma} is distinctly uncommon.17–19 Production of IFN-{gamma} by lymphocytes in response to the antigenic challenge of the melanoma tumor could help explain the apparently contradictory finding of suppressed IFN-{gamma} levels in the melanoma patients as a group, but increased levels in the melanoma patients who experienced disease recurrence. Although IFN-{gamma} is generally considered to enhance antitumor immunity, it is not effective as monotherapy for melanoma patients with established metastatic disease. Furthermore, in a phase III randomized trial of IFN-{gamma} as adjuvant therapy in high-risk melanoma patients, there was a trend toward a poorer disease-free and overall survival in the patients who received IFN-{gamma}.20 IFN-{gamma} has been shown to increase HLA class II expression both on lymphocytes from melanoma patients21 and on melanoma tumor cells.22–24 Increased HLA class II antigen expression is found both on thicker primary melanoma tumors and on melanoma metastases25–27; increased HLA class II expression by tumor cells has complex immunological effects, which can include the induction of immune tolerance.3,28 It is therefore plausible that increased HLA class II expression by melanoma tumors induced by high IFN-{gamma} levels could result in impaired immunorecognition of melanoma tumors and increased risk of disease progression. Measurement of IFN-{gamma} levels should be performed in a cohort of melanoma patients both before and after disease recurrence and at all stages of disease. Identification of HLA class II alleles and determination of HLA class II expression should be correlated with cytokine production in these patients.

Cytokine gene polymorphisms could help explain the associations between cytokine levels and melanoma incidence and progression identified in this study. Allelic variants of IFN-{gamma} genes have been identified.29,30 Allelic variants of IFN-{gamma} include promotor region polymorphisms associated with altered levels of cytokine production.29 Allelic variants of IFN-{gamma} have been linked to an altered risk of development of type I diabetes mellitus.31 Genetic polymorphisms in IFN-{gamma} genes should be investigated in a cohort of melanoma patients and correlated with cytokine levels and risk of disease recurrence.

Although polymorphisms in IFNG genes could help explain the independent association of increased IFN-{gamma} levels with melanoma recurrence observed in this study, IFN-{gamma} polymorphisms cannot easily explain the association of IFN-{gamma} levels with HLA-DRB1*1101. Linkage between these two genes is unlikely, because they reside on different chromosomes. Because HLA class II alleles can differentially regulate cytokine production, it is reasonable to hypothesize that HLA-DRB1*1101 may help regulate IFN-{gamma} levels in melanoma patients. Specific HLA class II alleles have been linked to differential cytokine production in specific disease states, notably HLA-DQB1*0302 and IFN-{gamma} production in type I diabetes mellitus.14 Potential HLA class II allele-specific regulation of IFN-{gamma} production should be investigated in melanoma patients.

In summary, we have identified increased preoperative plasma IFN-{gamma} levels as an independent predictor of recurrence in melanoma patients presenting with clinically localized disease. We have also identified at least one HLA class II allele, HLA-DRB1*1101, which is an independent predictor of melanoma recurrence in these patients. Finally, we have determined that patients who carry the HLA-DRB1*1101 gene have relatively increased levels of IFN-{gamma}. These results suggest that the presence of increased IFN-{gamma} levels, HLA-DRB1*1101, or both could identify relatively high-risk subgroups within an otherwise low-risk melanoma patient population, that HLA-DRB1*1101 could regulate IFN-{gamma} production in melanoma patients, and that this genetically controlled immune mechanism could help determine the risk of melanoma recurrence. HLA class II–mediated IFN-{gamma} production may be a target for immunotherapy of melanoma patients.


   Acknowledgments
 
The authors thank Lisa Garcia for manuscript preparation.


   Footnotes
 
Presented at the 53rd annual meeting of the Society of Surgical Oncology, Washington, DC, March 16, 2001.

Received for publication October 5, 2001. Accepted for publication March 29, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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H. K. G. Machulla, F. Steinborn, M. Tschigrjai, J. Langner, and N. G. Rainov
Meningioma: Is There an Association with Human Leukocyte Antigens?
Cancer Epidemiol. Biomarkers Prev., December 1, 2003; 12(12): 1438 - 1442.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
V. K. Sondak and A. E. Chang
Melanoma and Human Leukocyte Antigen Status: The Missing Link?
Ann. Surg. Oncol., October 1, 2002; 9(8): 723 - 724.
[Full Text] [PDF]

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