Editors' ChoiceImmunotherapy

The Chicken or the Egg? Checkpoint Markers Identify Tumor-Specific T Cells in Melanoma

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Science Translational Medicine  09 Apr 2014:
Vol. 6, Issue 231, pp. 231ec63
DOI: 10.1126/scitranslmed.3009047

Unlike most cancer treatments, blockade of immune checkpoints such as PD-1 and CTLA-4 is a therapy in which the primary mechanism of action of the drug is not the primary mechanism of efficacy; tumor regression is mediated by the endogenous T cell response against the tumor. But up until now, we have not been able to definitively connect the dots—that is, to identify which T cells kill the tumor and, as a corollary, what antigens in the tumor the T cells actually recognize. Now, Gros and colleagues have shown that expression of PD-1 on tumor-infiltrating lymphocytes (TILs) in melanoma identifies the T cells that specifically recognize tumor proteins, that this system can be used find the antigens, and that often, these antigens are mutated proteins specific to the patient’s tumor.

First, the authors found that compared with peripheral blood T cells, tumor-infiltrating T cells isolated from 24 melanoma samples express more PD-1, TIM-3, and LAG-3 (all inhibitory receptors). Then, the investigators sorted freshly isolated TILs according to expression of PD-1, LAG-3, and TIM-3; activated and cultured these TILs; and then tested their reactivity against autologous tumor cells. They found that nearly all the tumor-reactive cells were derived from the PD-1+, LAG-3+, and/or TIM-3+ TILs. On the basis of deep sequencing of the T cell receptor chains, the authors showed that the PD-1+ TILs had undergone clonal expansion and that these T cells were the ones that responded to patient-specific mutations.

The findings of Gros and coauthors suggest that sorting TILs based on PD-1 expression could serve as a platform for identifying tumor-specific antigens. Because the PD-1+ TILs included the greatest population of tumor-specific T cells, PD-1 blockade would likely unleash the widest immune repertoire; however, some of the tumor-specific T cells were TIM-3+, LAG-3+, or 4-1BB+, implying that targeting these receptors is likely to stimulate nonredundant tumor-specific T cells and may be synergistic with PD-1 blockade. The question is whether these strategies will apply to other tumors, because melanoma seems to recruit more TILs than other cancers and is especially sensitive to checkpoint blockade. When it comes to understanding the mechanism of immunotherapy, however, the answer is not the chicken or the egg, but the chicken and the egg: The clinical results of immunotherapy for cancer have directly enabled scientists to determine its mechanism, and understanding the mechanism should help to refine the clinical therapy.

A. Gros et al., PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 10.1172/JCI73639 (2014). [Full Text]

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