Engineered human pluripotent stem cell-derived natural killer cells with PD-L1 responsive immunological memory for enhanced immunotherapeutic efficacy

Adoptive chimeric antigen receptor(CAR)-engineered natural killer(NK)cells have shown promise in treating various cancers.However,limited immunological memory and access to sufficient numbers of allogenic donor cells have hindered their broader preclinical and clinical applications.Here,we first assess eight different CAR constructs that use an anti-PD-L1 nanobody and/or universal anti-fluorescein(FITC)single-chain variable fragment(scFv)to enhance antigen-specific proliferation and anti-tumor cytotoxicity of NK-92 cells against heterogenous solid tumors.We next genetically engineer human pluripotent stem cells(hPSCs)with optimized CARs and differentiate them into functional dual CAR-NK cells.The tumor microenvironment responsive anti-PD-L1 CAR effectively promoted hPSC-NK cell proliferation and cytotoxicity through antigen-dependent activation of phosphorylated STAT3(pSTAT3)and pSTAT5 signaling pathways via an intracellular truncated IL-2 receptorβ-chain(ΔIL-2Rβ)and STAT3-binding tyrosine-X-X-glutamine(YXXQ)motif.Anti-tumor activities of PD-L1-induced memory-like hPSC-NK cells were further boosted by administering a FITC-folate bi-specific adapter that bridges between a programmable anti-FITC CAR and folate receptor alpha-expressing breast tumor cells.Collectively,our hPSC CAR-NK engineering platform is modular and could constitute a realistic strategy to manufacture off-the-shelf CAR-NK cells with immunological memory-like phenotype for targeted immunotherapy.

Research Article Ferric iron coordinated cisplatin prodrug reprograms the immunecold tumor microenvironment through tumor hypoxia relief for enhanced cancer photodynamic-immunotherapy

The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.

Durable natural killer cell response after three doses of SARS-CoV-2 inactivated vaccine in HIV-infected individuals

Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccine can induce a potent cellular and humoral immune response to protect against SARS-CoV-2 infection.However,it was unknown whether SARS-CoV-2 vaccination can induce effective natural killer(NK)cell response in people living with human immunodeficiency virus(PLWH)and healthy individuals.Methods:Forty-seven PLWH and thirty healthy controls(HCs)inoculated with SARS-CoV-2 inactivated vaccine were enrolled from Beijing Youan Hospital in this study.The effect of SARS-CoV-2 vaccine on NK cell frequency,phenotype,and function in PLWH and HCs was evaluated by flow cytometry,and the response of NK cells to SARS-CoV-2 Omicron Spike(SARS-2-OS)protein stimulation was also evaluated.Results:SARS-CoV-2 vaccine inoculation elicited activation and degranulation of NK cells in PLWH,which peaked at 2 weeks and then decreased to a minimum at 12 weeks after the third dose of vaccine.However,in vitro stimulation of the corresponding peripheral blood monocular cells from PLWH with SARS-2-OS protein did not upregulate the expression of the aforementioned markers.Additionally,the frequencies of NK cells expressing the activation markers CD25 and CD69 in PLWH were significantly lower than those in HCs at 0,4 and 12 weeks,but the percentage of CD16^(+)NK cells in PLWH was significantly higher than that in HCs at 2,4 and 12 weeks after the third dose of vaccine.Interestingly,the frequency of CD16^(+)NK cells was significantly negatively correlated with the proportion of CD107a^(+)NK cells in PLWH at each time point after the third dose.Similarly,this phenomenon was also observed in HCs at 0,2,and 4 weeks after the third dose.Finally,regardless of whether NK cells were stimulated with SARS-2-OS or not,we did not observe any differences in the expression of NK cell degranulation markers between PLWH and HCs.Conclusions:SARS-CoV-2 vaccine elicited activation and degranulation of NK cells,indicating that the inoculation of SARS-CoV-2 vaccine enhances NK cell immune response.

Optimal approximation of linear systems by artificial immune response

This paper puts forward a novel artificial immune response algorithm for optimal approximation of linear systems. A quaternion model of artificial immune response is proposed for engineering computing. The model abstracts four elements, namely, antigen, antibody, reaction rules among antibodies, and driving algorithm describing how the rules are applied to antibodies, to simulate the process of immune response. Some reaction rules including clonal selection rules, immunological memory rules and immune regulation rules are introduced. Using the theorem of Markov chain, it is proofed that the new model is convergent. The experimental study on the optimal approximation of a stable linear system and an unstable one show that the approximate models searched by the new model have better performance indices than those obtained by some existing algorithms including the differential evolution algorithm and the multi-agent genetic algorithm.