TY - JOUR
T1 - Immunoregulatory effects of CD4+ T helper subsets in human melanoma
AU - Lee, Kyung Yung
AU - Goedegebuure, Peter S.
AU - Linehan, David C.
AU - Eberlein, Timothy J.
N1 - Funding Information:
ADOPTIVE IMMUNOTHERAPIES WITH TUMOR-INFILTRATING lymphocytes (TIL) and interleukin (IL)-2 have resulted in significant tumor regressions in selected patients with melanoma or with renal cell carcinoma (unpublished data)J,2 However, the overall response rate is only about 40% or less. An essential requirement for effective cellular immunotherapy is sufficient helper and cytolytic effector cell function at the tumor site. CD4 + T cells are of central importance in the regulation of both T and B cells, but little is known about the functional characteristics of human CD4 + TIL. In the murine system CD4 + T cells can be categorized into different subsets on the basis of cytokines that are produced after antigen activation), 4 T helper type 0 (Th0) Supported by National Institutes of Health grants CA45484 and CA09535, and by grant FRA-407 from the American Cancer Society. Dr. Eberlein is the recipient of an American Cancer Society Faculty Research Award. Accepted for publication Aug. 9, 1994. Reprint requests: Timothy J. Eberlein, MD, FACS, Department of Surgery, Division of Surgical Oncology, Brigham and Women's Hospital Harvard Medical School,7 5 Francis St., Boston, MA 02115. Copyright 9 1995 by Mosby-Year Book, Inc. 0039-6060/95/$3.00 + 0 11/56/59673 cells produce IL-2, IL-4, and interferon-% T helper type 1 (Thl) cells produce IL-2 and IFN-% whereas T helper type 2 (Th2) cells secrete IL-4, IL-5, IL-6, and IL-10. Thl cells mediate cellular and inflammatory responses, and Th2 cells support humoral responses) In recent studies human antigen-specific Thl-like and Th2-1ike clones were isolated from patients with tuberculoid leprosy 6 or atopy. 7 Also, an imbalance between Thl and Th2 responses has been attributed to immune dysregulation associated with the human immunodeficiency virus. 8 In contrast, the majority of CD4 + T-cell clones isolated from healthy donors were able to produce a Th0 profile of cytokines, 9 indicating that various diseases may be associated with a shift in Th-subset composition. Previously we described that the immune response in renal cell carcinoma is dominated by Th2 cells that do not produce IL-2) ~ In contrast, the CD4 + infiltrate in melanoma consists primarily of Th0 cells that do produce IL-2 among other cytokines) 1 The aim of the experiments described here was to study the immunoregulatory functions of CD4 + TIL clones generated from melanoma TIL. With five patients with melanoma, we generated tumor-specific cytotoxic CD8 + TIL with periodic autologous tumor stimulation and low-dose recombinant IL-2 (rIL-2).
PY - 1995/4
Y1 - 1995/4
N2 - Background. The elucidation of CD4+ T helper (Th) cell traits is important for the understanding of immunoregulatory mechanisms in patients with cancer, in particular the Th-cell effect on cytotoxic CD8+ tumor-specific lymphocytes (CTL). Methods. Sixty-six T-cell receptor αβ+/CD4+ clones were generated from tumor-infiltrating lymphocytes of five patients with melanoma and classified into subsets by cytokine production. Transwell experiments were performed to test how the soluble factors of each Th-clone subset affected the cytotoxicity of the tumor-specific CTL against autologous tumor. Results. Th0 clones enhanced cytotoxicity of the CD8+ CTL compared with control CTL cultured in cytokine-free medium. Th1-clone supernatant also enhanced cytotoxicity by CD8+ CTL. In contrast, Th2 clones decreased killing compared with control CTL. Replacement of the Th clones by exogenous interleukin (IL)-2 in concentrations similar to that produced by Th0 and Th1 clones enhanced cytotoxicity. However, suppression of cytotoxicity was observed when similar concentrations of IL-4 were added instead. The helper effect of Th0-soluble factors could be inhibited by anti-IL-2 antibody, whereas anti-IL-4 antibody did not show a significant enhancement. Conclusions. The majority of the CD4+ tumor-infiltrating lymphocytes (Th0) in patients with melanoma enhance the CTL response to autologous tumor by their soluble factors, whereas Th2 cells suppress the CTL response.
AB - Background. The elucidation of CD4+ T helper (Th) cell traits is important for the understanding of immunoregulatory mechanisms in patients with cancer, in particular the Th-cell effect on cytotoxic CD8+ tumor-specific lymphocytes (CTL). Methods. Sixty-six T-cell receptor αβ+/CD4+ clones were generated from tumor-infiltrating lymphocytes of five patients with melanoma and classified into subsets by cytokine production. Transwell experiments were performed to test how the soluble factors of each Th-clone subset affected the cytotoxicity of the tumor-specific CTL against autologous tumor. Results. Th0 clones enhanced cytotoxicity of the CD8+ CTL compared with control CTL cultured in cytokine-free medium. Th1-clone supernatant also enhanced cytotoxicity by CD8+ CTL. In contrast, Th2 clones decreased killing compared with control CTL. Replacement of the Th clones by exogenous interleukin (IL)-2 in concentrations similar to that produced by Th0 and Th1 clones enhanced cytotoxicity. However, suppression of cytotoxicity was observed when similar concentrations of IL-4 were added instead. The helper effect of Th0-soluble factors could be inhibited by anti-IL-2 antibody, whereas anti-IL-4 antibody did not show a significant enhancement. Conclusions. The majority of the CD4+ tumor-infiltrating lymphocytes (Th0) in patients with melanoma enhance the CTL response to autologous tumor by their soluble factors, whereas Th2 cells suppress the CTL response.
UR - http://www.scopus.com/inward/record.url?scp=0028956618&partnerID=8YFLogxK
U2 - 10.1016/S0039-6060(05)80054-6
DO - 10.1016/S0039-6060(05)80054-6
M3 - Article
C2 - 7716716
AN - SCOPUS:0028956618
SN - 0039-6060
VL - 117
SP - 365
EP - 372
JO - Surgery
JF - Surgery
IS - 4
ER -