| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Editorial |
From the Clinical Immunology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Joan and Sanford I Weill Medical College of Cornell University, New York, New York.
CD4+ T helper (Th) cells have been found to exist in three or more groups.1 Th1 cells preferentially stimulate cell-mediated immunity through production of interleukin-2 (IL-2), which causes their continued proliferation as well as activating CD8+ cytotoxic T lymphocytes (CTL). They also produce interferon gamma (IFN
), which inhibits Th2 cells. Th2 cells produce IL-4 and IL-10, which stimulate B cells and inhibit the Th1 response. A third type of cells, Th0, combines the cytokine profiles of both types of cells. A number of factors determine which phenotype is preferentially expressed. These include the affinity of the T-cell epitope for major histocompatibility complex II, the antigen dose, the ligand density, the antigen-presenting cell, the strength of co-stimulation, and the cytokine and chemokine milieu.2,3
Several studies have shown a correlation between the generation of a Th1 response and antitumor activity. Examination of the cytokine profile in primary human melanoma suggests an association between a Th1 response and regression, whereas absence of regression or progression is associated with a Th2 response.4,5 Analysis of CD4+ tumor infiltrating lymphocyte clones from patients with metastatic melanoma revealed a predominance of Th0 clones. Both Th0 and Th1 clones increased the activity of tumor-specific CTL clones, whereas Th2 clones caused a decrease.6,7 Further data in animals support the protective role of a Th1 response. Use of the poorly immunogenic murine melanoma B16 as a tumor vaccine leads to memory T cells in draining lymph nodes that secrete IL-4 and IL-10, and are not protective against tumor challenge. Immunization with the tumor, after transfection with an allogeneic class I gene, induces a protective type 1 response.8 Th2 cells generated in mice immunized with B16F10, a tumor strain with high metastatic potential, increase the metastatic potential of the low metastatic strain B16F1, which typically induces a Th1 response.9 In other models, both Th1 and Th2 responses are required, which emphasizes the role in tumor immunity of CD8-independent mechanisms, including CD4+ cells, potential type 1 effectors (e.g., macrophages), and type 2 effectors (e.g., eosinophils).10
In this issue of the Annals of Surgical Oncology, Hsueh et al.11 describe a correlation between the pretreatment in vitro Th2 response to the Canvaxin immunotherapeutic and survival of patients with American Joint Commission on Cancer (AJCC) stage III melanoma who subsequently receive Canvaxin. Canvaxin is an irradiated preparation of whole cell melanoma cells from three allogeneic melanoma cell lines. Th1 and Th2 responses were detected using an intracellular cytokine assay, which can detect antigen-specific responses without the need for prolonged in vitro stimulation. In prior studies, this group has shown that immunization with Canvaxin induces antibody and delayed-type hypersensitivity responses that correlate with increased survival.12,13 What is novel about the current study is that CD4+ T-cell responses before administration of Canvaxin correlated with survival. Furthermore, in a multivariate analysis, only the pre-Canvaxin CD4+ T-cell IL-4 responses (i.e., Th2 responses) were predictive of survival. Longer survival correlated with higher levels of Canvaxin-specific IL-4 secreting CD4+ T cells at baseline. The implication of this study is that a preexisting Th2 response to one or more antigens expressed by the whole cell vaccine is enhanced by administration of the vaccine. These results may also explain the earlier reports of a correlation between antibody responses to Canvaxin and prolonged survival.13 As noted by the authors, these observations require further confirmation in an ongoing phase III trial. These findings are also important because prior observational studies have suggested the predominance of Th1 responses in antitumor immunity. This has led to an effort by several groups to develop vaccines that specifically induce CD8+ T-cell responses. This study highlights the fact that an optimal antitumor vaccine should target not only CTL, but also both Th1 and Th2 CD4+ T-cells, as well as antibodies.14
A final note of interest in these studies is the correlation of immune responses with whole cell vaccines with survival, in contrast to the lack of clear correlation in several peptide vaccine trials between T-cell responses and clinical responses.15,16 The lack of correlation between T-cell responses and clinical responses in peptide vaccine trials may be caused by mechanisms of immune evasion or that most vaccines only target a limited number of epitopes.
FOOTNOTES
Received August 10, 2004; accepted August 23, 2004.
Address correspondence to: Jedd D. Wolchok, MD, PhD, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: 212-794-4352; E-mail wolchokj{at}mskcc.org.
REFERENCES
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
