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Annals of Surgical Oncology 9:82-87 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Cytokine Profiles of Sentinel Lymph Nodes Draining the Primary Melanoma

Stanley P. L. Leong, MD, Miao Peng, MD, Yuan-Ming Zhou, MD, Julio E. Vaquerano, MD and John W. C. Chang, MD

From the Department of Surgery, University of California at San Francisco Comprehensive Cancer Center (Mount Zion), San Francisco, California.

Correspondence: Address correspondence and reprint requests to: Stanley P. L. Leong, MD, Department of Surgery, University of California at San Francisco Comprehensive Cancer Center (Mount Zion), 1600 Divisadero St., #C333, San Francisco, CA 94143-1674; Fax: 415-353-7721; E-mail: leongs{at}surgery.ucsf.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: The sentinel lymph node (SLN) draining the primary melanoma is the first echelon node where micrometastasis is established. SLNs may be the initial sites of antigen presentation associated with immune responses.

Methods: A portion of each SLN from 68 melanoma patients undergoing selective SLN dissection was processed for enzyme-linked immunospot (ELISPOT) assay determination of interferon gamma (IFN-{gamma}), interleukin-2 (IL-2), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin-10 (IL-10) secretion. The control was the adjacent non-SLN. Lymphocytes were stimulated with staphylococcal enterotoxin A (SEA) prior to ELISPOT assay.

Results: No significant difference was noted in the production of IL-10 between the SLNs and non-SLNs. Significant production of IFN-{gamma}, IL-2, and GM-CSF was noted in the SLNs when compared to the non-SLNs in the overall group. Patients with no micrometastasis (n = 60) had elevated secretion of all cytokines in the SLNs. However, patients harboring lymph node micrometastasis (n = 8) showed no increase of cytokine secretion in the SLNs.

Conclusions: Significant Th1 and Th2 response was induced in melanoma-free SLNs.

Implications: SLNs without micrometastasis may be activated by submicroscopic cells or soluble tumor antigens, while cytokine production may be down-regulated by micrometastasis. Future studies should be directed towards identifying the specific SLN T cells recognizing the tumor antigens.

Key Words: Cytokines • Sentinel lymph node • Melanoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
The concept of the sentinel lymph node (SLN) as the first lymph node that drains a primary tumor site was first proposed by Cabanas in 1977 for penile carcinoma.1 The mapping of SLN has been successfully applied in the staging of primary malignant melanoma2 and breast cancer.3 Selective SLN dissection is a technique that harvests the lymph node draining the invasive primary melanoma and can spare as many as 80% of patients from a radical lymph node dissection.4 Because the SLN is the first lymph node that would be in contact with tumor cells or potential tumor antigens released by the tumor through lymphatic drainage, it is hypothesized that they are the first sites of tumor antigen presentation associated with lymphocyte activation. We hypothesize that activated lymphocytes in SLNs may show a different cytokine profile on stimulation when compared to lymphocytes in non-SLNs. Our aim is to compare the cytokine expression profile of lymphocytes from SLNs draining the primary melanoma with that from adjacent non-SLNs.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
Since the inception of the SLN program at the University of California at San Francisco (UCSF) Comprehensive Cancer Center (Mount Zion) in November of 1993, over 700 patients with Stage I/II primary melanoma (American Joint Committee on Cancer classification) have had preoperative lymphoscintigraphy and intraoperative mapping with resection of SLNs. The detailed method for selective SLN dissection has been previously described.5

The program at UCSF was initiated in November of 1993 when we joined the Multicenter Selective Lymphadenectomy Trial.6 After a total number of 42 patients on the trial, selective sentinel lymphadenectomy has evolved into a standard practice, and patients with lesions over 1.0 mm Breslow thickness are, therefore, recommended for the procedure. There was no requirement for the patients to sign informed consent outside the Multicenter Selective Lymphadenectomy Trial. In some cases, when the SLN specimen was dissected on a separate table, a non-SLN was found. Therefore, specimens were chosen for this study only when the SLN and non-SLN could be accurately identified. Those patients who had only SLNs harvested were not included in the study. Patients were not chosen in a strictly consecutive fashion, because not every consecutive specimen could fulfill this requirement. A total of 69 SLN and non-SLN pairs from the same nodal basin were obtained from 68 melanoma patients undergoing selective SLN dissection, with one patient having two SLN and non-SLN pairs harvested. The clinical and pathological characteristics of these patients are summarized in Table 1.


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  		TABLE 1. Clinical and pathologic characteristics of melanoma patients for SLN cytokine profiling (n = 68)
 
The protocol for processing the SLN included the bihalving of the SLN and placing the cut surface of the two halves onto a cassette with the external surface being painted with ink. The cassette was placed in 10% formalin. Several serial sections were made from the bottom of the cassette towards the ink surface for histologic evaluation using hematoxylin and eosin (H&E). Specific immunohistochemical staining for S-100 and HMB-45 was used when H&E sections were negative. The external surface of the lymph node towards the ink surface was usually not disturbed.7,8 Therefore, before processing the lymph node according to the method as mentioned above, a millimeter slice of the lymph node from the external surface was made for the preparation of the lymphocytes for this study. Because this external surface of the lymph node was not used for diagnostic purpose, the harvesting of this limited amount of the lymph node posed no diagnostic compromise to the patient (A. Cochran, personal communication, December 1999).

Enzyme-Linked Immunospot (ELISPOT) Assays
The lymph node tissue was collected in complete medium (CM) consisting of Roswell Park Memorial Institute (RPMI) 1640 medium (Irving Scientific, Santa Ana, CA), 10% fetal bovine serum (BioWhittaker Inc., Walkersville, MD), fungizone (2.5 µg/ml; BioWhittaker Inc.), streptomycin (100 µg/ml; BioWhittaker Inc.), and penicillin (100 units/ml; BioWhittaker Inc.). Using sterile technique, lymph node cells were released from the lymph node tissue using gentle pressure from the back of a 5-ml syringe barrel. Lymphocytes (2.5 x 105/200 µl medium/well in a 96-well plate) from SLNs and non-SLNs were first stimulated with staphylococcal enterotoxin A (SEA, 0.1 µg/ml, Sigma, St. Louis, MO) for 40 hours, and the plates were washed. Appropriate monoclonal antibodies (anti-IFN-{gamma}, anti-IL-2, anti-GM-CSF, and anti-IL-10; Endogen, Woburn, MA) were added, and an ELISPOT assay of interferon-{gamma} (IFN-{gamma}), interleukin-2 (IL-2), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin-10 (IL-10) was set up. Spots from each of the 96 wells were read by a digital quantification method.7 Briefly, 96-well nitrocellulose plates (HATF, MILLIPORE, Bedford, MA) were coated with 100 µl of primary antibody (Endogen, Woburn, MA) at 10 µg/ml diluted in sterile phosphate buffer saline (PBS) and incubated overnight at 4°C. Wells were washed with sterile PBS four times and were blocked with 200 µl of PBS + 10% FBS at 37°C for at least 30 minutes. The wells were filled with 100 µl of cell suspension (1 x 105 cells/well) and 100 µl of 0.1 µg/ml SEA solution. After incubation for 40 hours at 37°C and 5% CO2, cells were removed by washing four times with PBS, then washed four times with PBS containing 0.05% Tween 20 (BIO-RAD, Hercules, CA). One hundred µl of biotinylated secondary antibody were added to each well at 1 µg/ml (Endogen, Woburn, MA) in PBS + 4% BSA. After 1 hour of incubation at 37°C, the wells were washed four times with PBS-0.05% Tween 20. Subsequently, 100 µl of HRP-conjugated streptavidin (ZYMED, South San Francisco, CA) at 1:1000 dilution in PBS-0.05% Tween 20 was added for 30 minutes at room temperature. The wells were washed four times with PBS-Tween 20 before adding 100 µl of AEC substrate and incubating the plates for 5 minutes at room temperature. The substrate solution was discarded, and the plates were rinsed with tap water and air-dried. After the plates were allowed to dry for at least 30 minutes, the wells were read by the Alpha Imager system (Alpha Innotech Corp., San Leandro, CA).9

Software Program
Prophet Dot Graph (BBN Software Corporation, Cambridge, MA), a graphing and statistics program, was used to summarize the ELISPOT results for all cytokines studied.

Statistics
A two-tailed t-test was used to determine whether there was a significant difference between SLN and non-SLN cytokine production.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Figure 1 summarizes the expression profile of IFN-{gamma}, IL-2, GM-CSF, and IL-10 following SEA stimulation for 69 pairs of SLNs and non-SLNs. Significant production of IFN-{gamma}, IL-2, and GM-CSF was noted in the SLN cells versus the non-SLN cells. The lymph node pairs were separated into two groups based on the presence or absence of micrometastasis in the SLN as determined by H&E and immunohistochemical staining. For the pairs in which the SLN was negative for micrometastases (n = 61), as shown in Fig. 2A, significant elevation was noted for all four cytokines: IFN-{gamma} (P = .02); GM-CSF (P = .01); IL-2 (P = .04); and IL-10 (P = .03). For the group in which SLN was positive for micrometastases (n = 8), there was no significant difference between SLNs and non-SLNs for all the cytokines studied (Fig. 2B). Based on the pattern of the Prophet Dot Graph and analyzing the cytokine production in each pair with respect to each patient individually, a heterogeneous pattern of cytokine profiles was noted. Table 2 summarizes the distribution of individual cases of cytokine production (n = 61 pairs) with respect to three groups: (1) SLN > non-SLN; (2) no difference between SLN and non-SLN; and (3) SLN < non-SLN. A significant number of patients showed no difference between SLN and non-SLN with respect to the production of different cytokines. For IL-2, the total number of patients studied was only 46 rather than 60, because IL-2 was not included during the earlier part of the study. For IFN-{gamma}, 16 patients had production of SLN > NSLN, as compared to 7 patients with lower production in the SLNs. Likewise, more patients showed increased production of GM-CSF and IL-10 in SLN than in non-SLN, with 12 versus 5, and 14 versus 7, respectively. Of the 16 patients who had increased production of IFN-{gamma} in the SLN as compared to the non-SLN, 4 of those patients had a corresponding significant increase in IL-10, and 12 had no significant difference in IL-10 production with respect to the non-SLN levels. Table 3 summarizes the distribution of individual pairs of SLN versus non-SLN with respect to different patterns of cytokine production in 8 patients with SLNs harboring micrometastasis.



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  		FIG. 1. One SLN and non-SLN pair was obtained from each of 67 patients, and the 68th patient who yielded 2 pairs, giving a total of 69 pairs for analysis. ELISPOT assay was performed for IFN-{gamma}, IL-2, GM-CSF, and IL-10. A two-tailed t-test was used to compare cytokine production between SLNs and non-SLNs. Prophet Dot Graph showed significant production of IFN-{gamma} (P = .037), IL-2 (P = .036), and GM-CSF (P = .021) in SLN as compared to non-SLN. No difference was noted in IL-10 production.

 


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  		FIG. 2. When SLN pairs without micrometastasis were analyzed (n = 61), all cytokines were noted to be higher in SLNs than non-SLNs (A). On the other hand, no difference was noted in all cytokines (B) when micrometastasis was noted in the SLN pairs (n = 8).

 

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  		TABLE 2. Distribution of individual pairs with respect to different patterns of cytokine production in melanoma patients with negative SLN (n = 61)
 

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  		TABLE 3. Distribution of individual pairs with respect to different patterns of cytokine production in melanoma patients with positive SLN (n = 8)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
In human cancer, melanoma has been found to be antigenic.10 Immunotherapy has been tried extensively in human malignant melanoma because melanoma, in general, is resistant to both chemotherapy and radiotherapy. The use of autologous or allogenic melanoma vaccines has been shown to benefit patients without clinical disease when compared to historical controls,11 but randomized studies have not been able to demonstrate statistically significant benefits of patients receiving the tumor vaccines as compared with those receiving a placebo.12 Because of the limited benefit from active specific immunotherapy using autologous melanoma or allogenic melanoma vaccines, adoptive immunotherapy using lymphokine activated killer cells (LAK) or tumor infiltrated lymphocytes (TIL) has been attempted.13–15 Recently, we have used recombinant human GM-CSF as an adjuvant with autologous melanoma vaccine with some success.16 Part of the reason for the failure of immunotherapy against melanoma is that melanoma may produce immunosuppression in hosts. In fact, it has been shown that within the lymph node system, active immune response may be down-regulated.17–20 The sentinel lymphadenectomy technique allows us to detect metastasis at the microscopic level rather than palpable lymph nodes entirely replaced by melanoma. Therefore, a window of opportunity has emerged to study the host relationship to micrometastasis. This is the first paper that we are aware of investigating cytokine production in the SLN with the appropriate controls, i.e. the adjacent non-SLN.

We used SEA, a bacterial antigen and a stimulator for lymphocytes, because without SEA stimulation, no cytokine production could be detected. This is a nonspecific approach to see whether there are any activated lymphocytes available in the lymph node. On such nonspecific stimulation, those previously reactive lymphocytes may become activated by producing appropriate cytokines. On the other hand, the nonactivated lymphocytes usually are much less robust in producing cytokines. Ideally, specific antigen stimulation would be preferred, but none is available. Therefore, SEA is used to stimulate any reactive T cells with the capacity to produce cytokines. Such superantigens bind to MHC class II molecules to form ligands that interact with T-cell receptors of distinct Vß regions regardless of other variable components.21 Published data indicate that these staphylococcal enterotoxins stimulate both murine and human T cells of particular TCR Vß phenotypes.22

The overall comparison of cytokine levels between the SLNs and the non-SLNs is statistically significant using the two-tailed t-test. The variability of cytokine production in various SLNs indicates that there probably is a significant amount of heterogeneity among melanoma patients. The possible mechanism of heterogeneity with respect to sentinel responses to primary melanoma in different melanoma patients is beyond the scope of this paper. More sophisticated and sensitive molecular techniques will be required to determine whether such mechanisms exist.

Despite the variation and heterogeneity to be expected in melanoma, the overall cytokine production is suppressed in the SLNs with micrometastases as compared to those containing no micrometastases. Of course, differences such as the amount of micrometastasis, the relevance of the appropriate antigens from the primary melanoma, and the variation in the host response to the antigens could account for these variations. The interesting finding of our study is that when micrometastasis is found, the significance of cytokine production in the SLNs versus non-SLNs is not apparent, suggesting that immunosuppression may be initiated in the process of micrometastasis. To test this hypothesis, more positive SLNs need to be studied. On the other hand, without histologic evidence of micrometastasis, patterns of enhanced cytokine production are noted, suggesting that the lymphocytes may be stimulated either by a very small number of cells, which are not detectable by H&E, or by immunohistochemical staining. Also, it is possible that soluble antigens shed from the primary melanoma may serve as antigenic stimulation to enhance the immune reactivities of the lymphocytes. It will be interesting to expand this study with respect to three categories of patients: those with greater cytokine production in the SLN than in the non-SLN; those with no difference in cytokine production between the SLN and non-SLN; and those with greater cytokine secretion in the non-SLN than in the SLN, which may reflect a state of immunosuppression. These groups, as characterized by immunological findings, subsequently may be correlated with their clinical outcome. Because this is the first attempt to evaluate the cytokine production by lymphocytes in SLNs, no effort has been made to use specific antigenic stimulation method to test for cytokine production. Therefore, it is assumed that if the lymphocytes have been activated, they would respond to the SEA stimulation. Future studies will be pursued to address the issue of specificity by correlating cytokine production in response to peptide antigens such as MART-1, tyrosinase, MAGE-1, and other recently defined melanoma-associated antigenic peptides with respect to the antigenic profile of the primary melanoma.

Antigen-primed helper T lymphocytes can be classified into subsets of Th1 and Th2 cells. Th1 cells secrete IL-2 and IFN-{gamma} and play a major role in generating cell-mediated immunity such as delayed hypersensitivity reaction and the generation of cytotoxic T cells, which are important for destroying cancer and virally infected cells. Th2 lymphocytes secrete IL-4, IL-5, IL-10, and IL-13, all of which play a key role in augmenting antibody production by lymphocytes. Furthermore, these cytokines are important for the generation of inflammatory responses characterized by eosinophil and mast cell infiltration such as is observed in allergic hypersensitivity and defense against helminthic parasites.23,24 Both subsets may secrete GM-CSF to enhance proliferation and activation of dendritic cells. Although Th1 and Th2 cells are classified in terms of specific cytokines, their interactions are complicated, and the relationship between specific antigens and the corresponding production of cytokines, especially in cancer immunology, is not fully understood.25 There appears to be no overall increase in cytokine production in lymphocytes obtained from SLNs harboring micrometastasis, suggesting a generalized down-regulation by micrometastasis. On the other hand, when SLNs show no evidence of micrometastasis by H&E and immunohistochemistry, there is significant overall production of Th1 (IFN-{gamma} and IL-2) and Th2 (GM-CSF and IL-10) types of cytokines, as shown by a two-tail t-test (IFN-{gamma}, P = .02; IL-2, P = .04; GM-CSF, P = .01; IL-10, P = .03). The cytokine production by lymphocytes within the microenvironment of the SLN may be influenced differently by the primary tumor versus its metastasis within the SLN.

Studying the SLNs draining the primary melanoma with currently available molecular and immunological techniques has set the stage for further investigation of the interaction of the host lymph nodes draining the primary melanoma with respect to the soluble antigens being released and to the effect of micrometastasis.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
We conclude that significant immune reactivity is induced in the melanoma-free SLNs draining the primary melanoma. It is hypothesized that melanoma SLNs without micrometastasis, as defined by H&E and immunohistochemical staining, may be stimulated by submicroscopic tumor cells or soluble tumor antigens to produce more cytokines, whereas cytokine production may be down-regulated by micrometastasis. Future studies should be directed to the identification of the specific T cells from SLNs recognizing the tumor antigens.


   Acknowledgments
 
This study was supported in part by a grant from the Eva B. Buck Charitable Trust.


   Footnotes
 
Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16–19, 2000.

Received for publication March 17, 2000. Accepted for publication October 2, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

  1. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456–66.[CrossRef][Medline]
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  3. Giuliano AE. Mapping a pathway for axillary staging: a personal perspective on the current status of sentinel lymph node dissection for breast cancer. Arch Surg 1999; 134: 195–9.[Free Full Text]
  4. Leong SPL. The role of sentinel lymph node in human solid cancer.In: DeVita VT, Hellman S, Rosenberg S (eds). PPO Updates. Vol 12,No 4. Philadelphia: Lippincott-Raven, 1998: 1–12.
  5. Leong SPL, Steinmetz I, Habib FA, et al. Optimal selective sentinel lymph node dissection in primary malignant melanoma. Arch Surg 1997; 132: 666–73.[Abstract]
  6. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Ann Surg 1999; 230: 453–65.[CrossRef][Medline]
  7. Treseler PA, Tauchi PS. Pathologic analysis of the sentinel lymph node. Surg Clin North Am 2000; 80: 1695–1719.[CrossRef][Medline]
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  9. Vaquerano JE, Peng M, Chang JWC, et al. Digital quantification of the enzyme-linked immunospot (ELISPOT). Biotechniques 1998; 25: 830–4, 836.[Medline]
  10. Leong SPL. Immunotherapy of malignant melanoma. Surg Clin North Am 1996; 76: 1355–81.[CrossRef][Medline]
  11. Barth A, Morton DL. Active specific immunotherapy of human melanoma.In: Leong SPL (ed). Immunotherapy of Malignant Melanoma. Austin, TX: R.G. Landes Company, 1996: 55–71.
  12. Wallack M, Muthukumaran S, Whooley B, et al. Favorable clinical responses in subsets of patients from a randomized, multi-institutional melanoma vaccine trial. Ann Surg Oncol 1995; 3: 110–7.[Abstract]
  13. Rosenberg SA, Lotze M, Muul L, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889.[Abstract]
  14. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report [see comments]. N Engl J Med 1988; 319: 1676–80.[Abstract]
  15. Rosenberg SA. Immunotherapy with recombinant cytokines and activated lymphocytes in patients with advanced cancer: Review of Surgery Branch, NCI experience.In: Salmon SE (ed). Adjuvant Therapy of Cancer: Proceedings of the 6th International Conference on Adjuvant Therapy of Cancer. Philadelphia: WB Saunders, 1990: 33–8.
  16. Leong SPL, Enders-Zohr P, Zhou YM, et al. Recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and autologous melanoma vaccine mediate tumor regression in patients with metastatic melanoma. J Immunother 1999; 22: 166–74.
  17. Farzad Z, McBride WH, Ogbechi H, et al. Lymphocytes from lymph nodes at different distances from human melanoma vary in their capacity to inhibit/enhance tumor cell growth in vitro. Melanoma Res 1997; 7 (Suppl 2): S59–65.
  18. Cochran AJ, Pihl E, Wen DR, et al. Zoned immune suppression of lymph nodes draining malignant melanoma: histologic and immunohistologic studies. J Natl Cancer Inst 1987; 78: 399–405.
  19. Hoon DS, Bowker RJ, Cochran AJ. Suppressor cell activity in melanoma-draining lymph nodes. Cancer Res 1987; 47: 1529–33.[Abstract/Free Full Text]
  20. Hoon DS, Korn EL, Cochran AJ. Variations in functional immunocompetence of individual tumor-draining lymph nodes in humans. Cancer Res 1987; 47: 1740–4.[Abstract/Free Full Text]
  21. Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science 1990; 248: 705–11.[Abstract/Free Full Text]
  22. Fleischer B. Superantigens. Apmis 1994; 102: 3–12.[Medline]
  23. Tepper RI, Levinson DA, Stanger BZ, et al. IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice. Cell 1990; 62: 457–67.[CrossRef][Medline]
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