NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Abstract

Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

Immune checkpoints and their inhibition in cancer and infectious diseases

“…However, it is still unclear whether the effects of PD‐L1 and PD‐L2 on PD‐1 downstream signaling are dependent on the cell type that expresses the ligand. A recent study suggested that PD‐L1 expressing murine NK cells can suppress DC maturation and activation, while having no direct effect on T‐cell activation . To our knowledge, this is the first report to suggest that not all PD‐L1 expressing cell types are capable of directly inhibiting T cells through PD‐1 ligation.…”

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

“…15 When NK cells were reduced, there was an increase in CD8 1 tumor-directed effector cells. Furthermore, when primed in the absence of NK cells, this population of CD8 1 effector T cells protected against tumor growth and formation of secondary tumors in mice that were rechallenged.…”

“…Furthermore, when primed in the absence of NK cells, this population of CD8 1 effector T cells protected against tumor growth and formation of secondary tumors in mice that were rechallenged. 15 Given this new regulatory function, the reduction of NK cells that occurs during daratumumab treatment may enhance the antitumor immune response. An increase in CD8 1 effector memory T cells was observed in patients treated with single-agent daratumumab.…”

Innate immune signaling and regulation in cancer immunotherapy

“…NK cells have been reported to contribute to tumor control in some settings [82], but in established B16 tumors NK cells also have been shown to have regulatory function resulting in immune suppression, in part through PD-L1 expression [83]. Similarly, γδT cells are capable of direct tumor recognition and in some circumstances can be activated to kill tumor cells, but at the same time γδT cells with regulatory function have been identified from human breast cancer tissues [84].…”