Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

Abstract

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.

Senescent cells: Living or dying is a matter of NK cells

“…The idea of making tumor cells more prone to NK cell killing is not new, but the finding that senescent cells are preferentially recognized and cleared by NK cells extends the field of application. NK cell‐based anticancer therapies are promising and NK cell immunotherapy should be considered as part of a prosenescence therapy. A combined treatment could be conceived in which tumor cells are forced to senescence and then removed by in vivo boosted NK cells or in vitro activated adoptively transferred NK cells.…”

“…114 The idea of making tumor cells more prone to NK cell killing is not new, but the finding that senescent cells are preferentially recognized and cleared by NK cells extends the field of application. NK cell-based anticancer therapies are promising 115,116…”

New avenues for melanoma immunotherapy: Natural Killer cells?

“…Similar to CTLA‐4, T reg cells express high levels of PD‐1 that acts stimulating their proliferation, thus its blockade could diminish their number and/or activity, increasing antitumour immune responses . Furthermore, chronic stimulation, typical of cancer, can lead to a persistent expression of PD‐1, that in turn causes a state of exhaustion in NK and T cells that can be partially reversed by PD‐1 blockade, as shown in murine models …”

“…5 Furthermore, chronic stimulation, typical of cancer, can lead to a persistent expression of PD-1, that in turn causes a state of exhaustion in NK and T cells that can be partially reversed by PD-1 blockade, as shown in murine models. 7,8 Other immune checkpoint receptors are normally expressed to maintain self-tolerance. Leucocytes antigen-3 (LAG-3) acts like CTLA-4 limiting effector T cells and augmenting regulatory T (T reg ) cell activities.…”

Improved Efficacy of Antibody Cancer Immunotherapeutics through Local and Sustained Delivery

“…[4][5][6] Recently,N Kc ell inactivation by the PD-1/PD-L1 blockade was discovered;t his is an ew therapeutic target for PD-1/PD-L1 CIs. [7] Other new CR targets, such as CD47 for cancers not amenable to PD-1, PD-L1, or CTLA-4 CI therapies, have also been identified. [8] Bispecific antibodies, such as bispecific Tcell engagers (BiTEs), simultaneously bind cancera ntigens and CD3 on CTLs, and this initiatesTcell-mediated tumor killing.…”