In Vivo Antitumor Efficacy of Tumor-Draining Lymph Node Cells Activated with Nonspecific T-Cell Reagents

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Abstract

Summary:

Progressive growth of immunogenic murine tumors elicits a tumor-specific but functionally deficient T-cell immune response in the draining lymph nodes. These T cells, referred to as “pre-effector” cells could be induced in vitro to differentiate into mature immune effector cells, capable of mediating the regression of established metastases. Initially, tumor cells were used to stimulate the in vitro maturation of pre-effector cells. Alternatively, we found that pre-effector cells could be activated by sequential stimulation with anti-CD3 and interleukin-2 in the absence of tumor cells. In adoptive immunotherapy, these activated cells mediated therapeutic effects that were exquisitely specific to the tumor that triggered the pre-effector cell response in vivo. Since the anti-CD3 interaction with T cells is polyclonal, the activated lymph node cell population must also contain a significant number of T cells that do not have tumor specificity. In an attempt to selectively activate tumor-sensitized pre-effector cells, we recently utilized superantigenic bacterial toxins as T-cell stimuli for effector cell generation. Superantigens combine with major histocompatibility class II molecules to form the ligands that stimulate T cells bearing distinct T-cell receptor Vp elements. Lymph node cells draining the MCA 205 sarcoma stimulated with staphylococcal enterotoxins A (SEA), B (SEB), or C2 (SEC2) resulted in selective expansions of Vβ3 and 11, Vβ 3 and 8, or Vβ 8.2 T cells, respectively. Adoptive immunotherapy experiments revealed that SEB- and SEC2-, but not SEA- stimulated cells, mediated tumorspecific eradication of pulmonary metastases. These results demonstrate the immunologic significance of bacterial superantigen interactions to the differentiation of sensitized T cells. Our results also suggest that T cells bearing Vβ 8 may more preferentially respond to the growing tumor than T cells bearing Vβ 3 or 11 elements of the T-cell receptor.

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