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Tumor antigen-specific T helper cells in cancer immunity and immunotherapy

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Abstract

Historically, cancer-directed immune-based therapies have focused on eliciting a cytotoxic T cell (CTL) response, primarily due to the fact that CTL can directly kill tumors. In addition, many putative tumor antigens are intracellular proteins, and CTL respond to peptides presented in the context of MHC class I which are most often derived from intracellular proteins. Recently, increasing importance is being given to the stimulation of a CD4+ T helper cell (Th) response in cancer immunotherapy. Th cells are central to the development of an immune response by activating antigen-specific effector cells and recruiting cells of the innate immune system such as macrophages and mast cells. Two predominant Th cell subtypes exist, Th1 and Th2. Th1 cells, characterized by secretion of IFN-γ and TNF-α, are primarily responsible for activating and regulating the development and persistence of CTL. In addition, Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC. Th2 cells favor a predominantly humoral response. Particularly important during Th differentiation is the cytokine environment at the site of antigen deposition or in the local lymph node. Th1 commitment relies on the local production of IL-12, and Th2 development is promoted by IL-4 in the absence of IL-12. Specifically modulating the Th1 cell response against a tumor antigen may lead to effective immune-based therapies. Th1 cells are already widely implicated in the tissue-specific destruction that occurs during the pathogenesis of autoimmune diseases, such as diabetes mellitus and multiple sclerosis. Th1 cells directly kill tumor cells via release of cytokines that activate death receptors on the tumor cell surface. We now know that cross-priming of the tumor-specific response by potent APC is a major mechanism of the developing endogenous immune response; therefore, even intracellular proteins can be presented in the context of MHC class II. Indeed, recent studies demonstrate the importance of cross-priming in eliciting CTL. Many vaccine strategies aim to stimulate the Th response specific for a tumor antigen. Early clinical trials have shown that focus on the Th effector arm of the immune system can result in significant levels of both antigen-specific Th cells and CTL, the generation of long lasting immunity, and a Th1 phenotype resulting in the development of epitope spreading.

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Abbreviations

ANN:

Artificial neural networks

APC:

Antigen-presenting cells

CTL:

Cytotoxic T cells

DC:

Dendritic cell

HLA:

Human leukocyte antigen

IFN:

Interferon

IL:

Interleukin

TCR:

T cell receptor

Th:

T helper

Th1:

T helper 1

Th2:

T helper 2

TNF:

Tumor necrosis factor

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Acknowledgements

KLK is supported by grants from the Department of Defense Breast Cancer Program (DAMD 17-03-1-0727) and NCI grants R21CA105270 and R41CA107590. MLD is supported for this work by NCI grant K24CA85218 and the Avon Foundation. We thank Mr. Robert Schroeder for assistance in manuscript preparation.

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  1. Department of Immunology, Mayo Clinic College of Medicine, 342C Guggenheim Bldg., 200 First St. SW, Rochester, MN, 55906, USA

    K. L. Knutson

  2. Tumor Vaccine Group, Oncology, University of Washington, 1959 NE Pacific Street, Box 356527, Seattle, WA, 98195-6527, USA

    M. L. Disis

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Correspondence to K. L. Knutson.

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Knutson, K.L., Disis, M.L. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54, 721–728 (2005). https://doi.org/10.1007/s00262-004-0653-2

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