CD4⁺T cells eliminate MHC class II-negative cancer cellsin vivoby indirect effects of IFN-γ

Abstract

CD4 + T cells can eliminate tumor cells in vivo in the absence of CD8 + T cells. We have CD4 + T cells specific for a MHC class II-restricted, tumor-specific peptide derived from a mutant ribosomal protein expressed by the UV light-induced tumor 6132A-PRO. By using neutralizing mAb specific for murine IFN-γ and adoptive transfer of CD4 + T cells into severe combined immunodeficient mice, we show that anti-IFN-γ treatment abolishes the CD4 + T cell-mediated rejection of the tumor cells in vivo . The tumor cells were MHC class II negative, and IFN-γ did not induce MHC class II expression in vitro . Therefore, the tumor-specific antigenic peptide must be presented by host cells and not the tumor cells. Tumor cells transduced to secrete IFN-γ had a markedly reduced growth rate in severe combined immunodeficient mice, but IFN-γ did not inhibit the growth of the tumor cells in vitro . Furthermore, tumor cells stably expressing a dominant-negative truncated form of the murine IFN-γ receptor α chain, and therefore insensitive to IFN-γ, nevertheless were rejected by the adoptively transferred CD4 + T cells. Thus, host cells, and not tumor cells, seem to be the target of IFN-γ. Together, these results show that CD4 + T cells can eliminate IFN-γ-insensitive, MHC class II-negative cancer cells by an indirect mechanism that depends on IFN-γ.

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

“…Taken together these data indicate that vaccination may direct potent inflammatory response to the tumour itself or to tumour draining lymph nodes. Induction of tumour-specific Th cells is considered also to be mandatory for establishing and maintaining a clinically efficient anticancer immune response caused by CTLs (Mumberg et al, 1999;Schurmans et al, 2001) Vaccine induced Th cells, may interact with professional APCs (i.e. dendritic cells) that have engulfed dead tumour tissue, in situ in the tumour or in draining lymph nodes.…”

“…The telomerase peptide used in this study, GV1001; hTERT (611 -626) is a promiscuous HLA class II epitope, a property making GV1001 a candidate for a general cancer vaccine that may, in contrast to many other peptide-based vaccines, be administered without prior HLA typing of the patients. Most tumours do not express HLA class II molecules on their surface but HLA class II restricted CD4 þ T cells are nevertheless considered to be mandatory for establishing and maintaining a clinically efficient anticancer immune response (Mumberg et al, 1999;Schurmans et al, 2001).…”

Clinical significance of immune cell infiltration within gallbladder cancer

“…Overall immune responses, however, were too weak and transient to eradicate cancer cells in the majority of patients receiving immunisation (Wang, 2001). Therefore, growing attention has been paid to the value of CD4 þ T cells (Mumberg et al, 1999;Marzo et al, 2000;Beatty and Paterson, 2001;Wang, 2001) and DCs (Lespagnard et al, 1999;Almand et al, 2000) in antitumour immunity.…”

“…In contrast to CD8 þ T cells, CD4 þ T cells recognise tumour-specific antigenic peptides on MHC class II molecules via an exogenous processing pathway (Larsson et al, 2001). Cytokines, such as IL-2 or IFN-gamma, released by CD4 þ T cells upon antigenic stimulation are important for the antitumour effects of activated CD4 þ T cells in vivo (Mumberg et al, 1999;Marzo et al, 2000;Beatty and Paterson, 2001). Activation of both T-cell subsets requires the presentation of antigenic peptides on professional antigen-presenting cells (APCs) (Larsson et al, 2001).…”

Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma

“…Essentially, CD4 þ T cells recognise peptides presented on MHC class II molecules expressed primarily on antigen-presenting cells. Although most tumour cells do not express MHC class II molecules, CD4 þ T cells can effect an antitumour response in the absence of CD8 þ T cells by secreting cytokines, such as interferon-g (Mumberg et al, 1999;Qin and Blankenstein, 2000), or by activation and recruitment of effector cells such as macrophages and eosinophils (Greenberg, 1991;Hung et al, 1998). However, the main role of CD4 þ T cells in the immune response to cancer is to prime CD8 þ cells and maintain their proliferation.…”