Helper-Independent, L-Selectinlow CD8+ T Cells with Broad Anti-Tumor Efficacy Are Naturally Sensitized During Tumor Progression

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Abstract
We recently reported that the CD4+ T cell subset with low L-selectin expression (CD62Llow) in tumor-draining lymph nodes (TDLN) can be culture activated and adoptively transferred to eradicate established pulmonary and intracranial tumors in syngeneic mice, even without coadministration of IL-2. We have extended these studies to characterize the small subset of L-selectinlow CD8+ T cells naturally present in TDLN of mice bearing weakly immunogenic tumors. Isolated L-selectinlow CD8+ T cells displayed the functional phenotype of helper-independent T cells, and when adoptively transferred could consistently eradicate, like L-selectinlow CD4+ T cells, both established pulmonary and intracranial tumors without coadministration of exogenous IL-2. Whereas adoptively transferred L-selectinlow CD4+ T cells were more potent on a cell number basis for eradicating 3-day intracranial and s.c. tumors, L-selectinlow CD8+ T cells were more potent against advanced (10-day) pulmonary metastases. Although the presence of CD4+ T cells enhanced generation of L-selectinlow CD8+ effector T cells, the latter could also be obtained from CD4 knockout mice or normal mice in vivo depleted of CD4+ T cells before tumor sensitization. Culture-activated L-selectinlow CD8+ T cells did not lyse relevant tumor targets in vitro, but secreted IFN-γ and GM-CSF when specifically stimulated with relevant tumor preparations. These data indicate that even without specific vaccine maneuvers, progressive tumor growth leads to independent sensitization of both CD4+ and CD8+ anti-tumor T cells in TDLN, phenotypically L-selectinlow at the time of harvest, each of which requires only culture activation to unmask highly potent stand-alone effector function.

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