T cell homeostatic proliferation elicits effective antitumor autoimmunity

Wolfgang Dummer

Andreas Niethammer

Roberto Baccala

Brian Lawson

Norbert Wagner

Ralph Reisfeld

Argyrios Theofilopoulos

^{Department of Immunology, The Scripps Research Institute, La Jolla, California, USA}^{Department of Pediatrics, Klinikum Dortmund, Dortmund, Germany}

Address correspondence to: Argyrios N. Theofilopoulos, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd/IMM3, La Jolla, California 92037, USA. Phone: (858) 784-8135; Fax: (858) 784-8361; E-mail: ude.sppircs@oirygra.

Received 2002 Feb 1; Accepted 2002 May 28.

Abstract

Development of tumor immunotherapies focuses on inducing autoimmune responses against tumor-associated self-antigens primarily encoded by normal, unmutated genes. We hypothesized that such responses could be elicited by T cell homeostatic proliferation in the periphery, involving expansion of T cells recognizing self-MHC/peptide ligands. Herein, we demonstrate that sublethally irradiated lymphopenic mice transfused with autologous or syngeneic T cells showed tumor growth inhibition when challenged with melanoma or colon carcinoma cells. Importantly, the antitumor response depended on homeostatic expansion of a polyclonal T cell population within lymph nodes. This response was effective even for established tumors, was characterized by CD8^{T cell–mediated tumor-specific cytotoxicity and IFN-γ production, and was associated with long-term memory. The results indicate that concomitant induction of the physiologic processes of homeostatic T cell proliferation and tumor antigen presentation in lymph nodes triggers a beneficial antitumor autoimmune response.}

Abstract

Acknowledgments

This is manuscript number 14647IMM from the Department of Immunology, The Scripps Research Institute. The work of the authors reported herein was supported by NIH grants AR-39555, AR-31203, and AG-15061 (A.N. Theofilopoulos), and NIH grant CA-83856 and funds from the Cancer Research Fund under Interagency Agreement 2110020 (University of California Contract 00-0078V, to R.A. Reisfeld). A.G. Niethammer is a fellow of the Deutsche Krebshife.

Acknowledgments

Footnotes

See the related Commentary beginning on page 157.

Wolfgang Dummer and Andreas G. Niethammer contributed equally to this work.

Conflict of interest: No conflict of interest has been declared.

Nonstandard abbreviations used: dendritic cells (DCs); lymph node (LN); carboxyfluorescein-diacetate-succinimidyl-ester (CFSE); recombination-activating gene–deficient (RAG-deficient).

Footnotes

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