A Population of Innate Lymphoid Cells Impairs TIL Expansion in HGSC

Innate lymphoid cells (ILC) regulate adaptive T-cell responses, but the role of ILCs, especially non-NK ILCs, in regulating antitumor T cells is not well defined. Crome and colleagues identified a distinct CD56⁺CD3⁻ population of ILCs that were associated with reduced tumor-infiltrating lymphocyte (TIL) expansion in cultures from primary high-grade serous cancer (HGSC), resulting in insufficient expansion for adoptive cell therapy. CD56⁺CD3⁻ ILCs from slow-growing TIL cultures were capable of directly suppressing T-cell proliferation, whereas CD56⁺CD3⁻ ILCs from rapidly expanding TIL cultures were not, suggesting the existence of a distinct CD56⁺CD3⁻ regulatory subpopulation. RNA sequencing of TIL cultures from 6 donors revealed distinct but overlapping gene expression signatures in regulatory versus nonregulatory CD56⁺CD3⁻ ILCs. The expression profiles overlapped with those of natural killer (NK) cells, including high expression of NCR1 (encoding NKp46). Treatment of regulatory CD56⁺CD3⁻ ILCs with an anti-NKp46 antibody prevented the suppression of T-cell expansion. The regulatory CD56⁺CD3⁻ ILCs capable of suppressing TIL expansion secreted high levels of the cytokines IL9 and IL22, whereas stimulated nonregulatory CD56⁺CD3⁻ ILCs did not produce IL22. Although the regulatory ILCs expressed high levels of genes associated with cytotoxicity, including granzyme A, granzyme B, and perforin, they exhibited low cytotoxic activity. To determine if regulatory CD56⁺CD3⁻ ILC–mediated suppression of TILs promoted immune evasion, clinical outcomes were compared in patients with and without regulatory CD56⁺CD3⁻ ILC populations. The average time to recurrence was 12.6 months in patients with regulatory CD56⁺CD3⁻ ILCs compared with 24 months in patients without regulatory CD56⁺CD3⁻ ILCs in their TIL cultures. Altogether, these results identify a population of CD56⁺CD3⁻ ILCs that suppress expansion of antitumor TILs and may be a negative prognostic biomarker in patients with HGSC. Further, these findings suggest the possibility that depletion of regulatory ILCs may improve immune surveillance to enhance adoptive T-cell immunotherapy.

Crome SQ, Nguyen LT, Lopez-Verges S, Yang SY, Martin B, Yam JY, et al. A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 2017 Feb 6 [Epub ahead of print].