Abstract
To characterize the nature of the local cytokine response to cancer, we chose to investigate cytokine patterns in biopsy specimens of basal cell carcinoma (BCC). We hypothesized that a distinct pattern of local cytokine production may be characteristic of BCC, a neoplasia of epidermis, in comparison to the pattern of seborrheic keratosis (SK), a benign growth of epidermis. We analyzed cytokine mRNAs in BCC versus SK by performing polymerase chain reaction on mRNA derived from biopsy specimens. The mRNAs encoding cytokines for IL-4, IL-5, IL-10, and granulocyte macrophage colony-stimulating factor were strongly expressed in BCC lesions and weakly expressed in SK lesions. Conversely, IL-2, IFN-gamma, and lymphotoxin mRNAs were strongly expressed in SK lesions and weakly expressed in BCC lesions. The response to malignancy, BCC, was typified by cytokines characteristic of murine TH2 cells. This cytokine pattern favors humoral immunity with concomitant immunosuppression of cell-mediated immune responses. In comparison, the response to the benign growth, SK, was typified by cytokines characteristic of murine TH1 cells that favor cell-mediated immune reactions. The findings of a distinct cytokine pattern in skin cancer provide a framework to develop strategies for immunologic intervention.
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- Belldegrun A., Kasid A., Uppenkamp M., Topalian S. L., Rosenberg S. A. Human tumor infiltrating lymphocytes. Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy. J Immunol. 1989 Jun 15;142(12):4520–4526. [PubMed] [Google Scholar]
- Ben-Sasson S. Z., Le Gros G., Conrad D. H., Finkelman F. D., Paul W. E. Cross-linking Fc receptors stimulate splenic non-B, non-T cells to secrete interleukin 4 and other lymphokines. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1421–1425. doi: 10.1073/pnas.87.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bloom B. R., Salgame P., Diamond B. Revisiting and revising suppressor T cells. Immunol Today. 1992 Apr;13(4):131–136. doi: 10.1016/0167-5699(92)90110-S. [DOI] [PubMed] [Google Scholar]
- Cornell R. C., Greenway H. T., Tucker S. B., Edwards L., Ashworth S., Vance J. C., Tanner D. J., Taylor E. L., Smiles K. A., Peets E. A. Intralesional interferon therapy for basal cell carcinoma. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):694–700. doi: 10.1016/0190-9622(90)70276-n. [DOI] [PubMed] [Google Scholar]
- Curson C., Weedon D. Spontaneous regression in basal cell carcinomas. J Cutan Pathol. 1979 Oct;6(5):432–437. doi: 10.1111/j.1600-0560.1979.tb01166.x. [DOI] [PubMed] [Google Scholar]
- Ebina N., Gallardo D., Shau H., Golub S. H. IL-1 and IL-4 as reciprocal regulators of IL-2 induced lymphocyte cytotoxicity. Br J Cancer. 1990 Oct;62(4):619–623. doi: 10.1038/bjc.1990.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Enk A. H., Katz S. I. Identification and induction of keratinocyte-derived IL-10. J Immunol. 1992 Jul 1;149(1):92–95. [PubMed] [Google Scholar]
- Fearon E. R., Pardoll D. M., Itaya T., Golumbek P., Levitsky H. I., Simons J. W., Karasuyama H., Vogelstein B., Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
- Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
- Gansbacher B., Zier K., Daniels B., Cronin K., Bannerji R., Gilboa E. Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med. 1990 Oct 1;172(4):1217–1224. doi: 10.1084/jem.172.4.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Golumbek P. T., Lazenby A. J., Levitsky H. I., Jaffee L. M., Karasuyama H., Baker M., Pardoll D. M. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science. 1991 Nov 1;254(5032):713–716. doi: 10.1126/science.1948050. [DOI] [PubMed] [Google Scholar]
- Grimwood R. E., Tharp M. D. Growth of human basal cell carcinomas transplanted to C57/Balb/C bgJ/bgJ nu/nu (beige-nude) mice. J Dermatol Surg Oncol. 1991 Aug;17(8):661–666. doi: 10.1111/j.1524-4725.1991.tb01316.x. [DOI] [PubMed] [Google Scholar]
- Hart P. H., Vitti G. F., Burgess D. R., Whitty G. A., Piccoli D. S., Hamilton J. A. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989 May;86(10):3803–3807. doi: 10.1073/pnas.86.10.3803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kapsenberg M. L., Wierenga E. A., Bos J. D., Jansen H. M. Functional subsets of allergen-reactive human CD4+ T cells. Immunol Today. 1991 Nov;12(11):392–395. doi: 10.1016/0167-5699(91)90137-I. [DOI] [PubMed] [Google Scholar]
- King C. L., Ottesen E. A., Nutman T. B. Cytokine regulation of antigen-driven immunoglobulin production in filarial parasite infections in humans. J Clin Invest. 1990 Jun;85(6):1810–1815. doi: 10.1172/JCI114639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kupper T., Flood P., Coleman D., Horowitz M. Growth of an interleukin 2/interleukin 4-dependent T cell line induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). J Immunol. 1987 Jun 15;138(12):4288–4292. [PubMed] [Google Scholar]
- Martinez O. M., Gibbons R. S., Garovoy M. R., Aronson F. R. IL-4 inhibits IL-2 receptor expression and IL-2-dependent proliferation of human T cells. J Immunol. 1990 Mar 15;144(6):2211–2215. [PubMed] [Google Scholar]
- Mihara M., Nakayama H., Nakamura K., Morimura T., Hagari Y., Shimao S. Histologic changes in superficial basal cell epithelioma and Bowen's disease by intralesional injection of recombinant interleukin 2: recombinant interleukin 2 may induce redifferentiation of malignant tumor cells in vivo. Arch Dermatol. 1990 Aug;126(8):1107–1107. doi: 10.1001/archderm.1990.01670320131032. [DOI] [PubMed] [Google Scholar]
- Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
- Mozzanica N., Cattaneo A., Boneschi V., Brambilla L., Melotti E., Finzi A. F. Immunohistological evaluation of basal cell carcinoma immunoinfiltrate during intralesional treatment with alpha 2-interferon. Arch Dermatol Res. 1990;282(5):311–317. doi: 10.1007/BF00375725. [DOI] [PubMed] [Google Scholar]
- Murray J. S., Madri J., Tite J., Carding S. R., Bottomly K. MHC control of CD4+ T cell subset activation. J Exp Med. 1989 Dec 1;170(6):2135–2140. doi: 10.1084/jem.170.6.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
- North R. J., Awwad M., Dunn P. L. The immune response to tumors. Transplant Proc. 1989 Feb;21(1 Pt 1):575–577. [PubMed] [Google Scholar]
- Pearce E. J., Caspar P., Grzych J. M., Lewis F. A., Sher A. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991 Jan 1;173(1):159–166. doi: 10.1084/jem.173.1.159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peleman R., Wu J., Fargeas C., Delespesse G. Recombinant interleukin 4 suppresses the production of interferon gamma by human mononuclear cells. J Exp Med. 1989 Nov 1;170(5):1751–1756. doi: 10.1084/jem.170.5.1751. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pond L., Wassom D. L., Hayes C. E. Evidence for differential induction of helper T cell subsets during Trichinella spiralis infection. J Immunol. 1989 Dec 15;143(12):4232–4237. [PubMed] [Google Scholar]
- Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
- Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., Simon P., Lotze M. T., Yang J. C., Seipp C. A. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. doi: 10.1056/NEJM198812223192527. [DOI] [PubMed] [Google Scholar]
- Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
- Simon J. C., Cruz P. D., Jr, Bergstresser P. R., Tigelaar R. E. Low dose ultraviolet B-irradiated Langerhans cells preferentially activate CD4+ cells of the T helper 2 subset. J Immunol. 1990 Oct 1;145(7):2087–2091. [PubMed] [Google Scholar]
- Sitz K. V., Keppen M., Johnson D. F. Metastatic basal cell carcinoma in acquired immunodeficiency syndrome-related complex. JAMA. 1987 Jan 16;257(3):340–343. [PubMed] [Google Scholar]
- Tank B., Habets J. M., Naafs B., Damsma O., Stolz E., van Joost T. Intralesional treatment of basal cell carcinoma with low-dose recombinant interferon gamma. J Am Acad Dermatol. 1989 Oct;21(4 Pt 1):734–735. doi: 10.1016/s0190-9622(89)70246-2. [DOI] [PubMed] [Google Scholar]
- Tepper R. I., Pattengale P. K., Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989 May 5;57(3):503–512. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
- Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wierenga E. A., Snoek M., de Groot C., Chrétien I., Bos J. D., Jansen H. M., Kapsenberg M. L. Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients. J Immunol. 1990 Jun 15;144(12):4651–4656. [PubMed] [Google Scholar]
- Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]