Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in combination therapies and lack of efficacy in monotherapies. Although NK cell-specific checkpoint targets such as NKG2A and KIRs are currently being evaluated in clinical trials, the clinical impact of NK cells on the PD1 cascade is less well understood compared to T cells. Furthermore, while NK cells have effector activity within the TME, under continuous ligand exposure, NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. Due to above-mentioned factors, we designed novel NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3ζ to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PD-L1⁺ target cells. Additionally, PD1-CSR⁺ NK cells infiltrated and killed tumor spheroids. While primary NK cells (pNK), expressing native PD1, showed decreased degranulation and cytokine production against PD-L1⁺ target cells by twofold, PD1-CSR⁺ pNK cells demonstrated increased activity upon PD-L1⁺ target cell recognition and enhanced antibody-dependent cellular cytotoxicity. PD1-CSR⁺ pNK cells from patients with MM increased degranulation and cytokine expression against autologous CD138⁺PD-L1⁺ malignant plasma cells. Taken together, the present results demonstrate that PD1-CSR⁺ NK cells enhance and sustain potent anti-tumor activity in a PD-L1⁺ microenvironment and thus represent a promising strategy to advance adoptive NK cell-based immunotherapies toward PD-L1⁺ cancers.

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