The relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus.
NK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification.
In CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors.
These findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.
Copyright © 2024 Selim, Suef, Saied, Abdel-Maksoud, Almutairi, Aufy, Mousa, Mansour and Farag.

Humanized tumour models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumour and immune system of human cancer. However, endogenous antitumour immunity in humanized models is still largely undefined.
We established an autologous humanized mouse tumour model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumours generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumours after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model.
We found human T cell subsets described in human cancer, including progenitor exhausted (Tpex), terminally exhausted (Tex-term) and tissue-resident (TRM) cells in tumour-bearing humanized mice with accumulation of Tex-term and TRM in the tumour. In addition, we identified tumour-reactive CD8+ T cells through expression of CD137. This subpopulation of de novo arising human CD137+ CD8+ T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 (B3GAT1) and cytolytic effector molecules such as PRF1, GZMH and NKG7. Moreover, these CD137+ CD8+ T cells exhibited tumour-specific clonal expansion and presented signature overlap with tumour-reactive CD8+ T cells described in human cancer. We demonstrate superior anticancer activity of this activated and exhausted-like human CD8+ T cell subset by adoptive transfer experiments using recipients bearing autologous human tumours. Mice adoptively transferred with CD137+ CD8+ T cells showed reduced tumour growth and higher CD8+ T cell tumour infiltration, correlating with control of human tumours.
We established an immunocompetent humanized tumour model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8+ T cells with an activated and exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies.
Swiss Cancer Research foundation.
Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Background Humanized tumor models could be particularly valuable for cancer immunotherapy research, as they may better reflect human-specific aspects of the interfaces between tumor and immune system of human cancer. However, endogenous antitumor immunity in humanized models is still largely undefined. Methods We established a novel autologous humanized mouse tumor model by using NSG mice reconstituted with human immune cells from hematopoietic progenitors and tumors generated from transformed autologous human B cells. We demonstrate growth of solid lymphoid tumors after subcutaneous implantation, infiltration by endogenous human immune cells and immunocompetence of the model. Findings We found human T cell subsets described in human cancer, including progenitor exhausted (T pex ), terminally exhausted (T ex-term ) and tissue-resident (T RM ) cells in tumor-bearing humanized mice with accumulation of T ex-term and T RM in the tumor. In addition, we identified tumor-reactive CD8 + T cells through expression of CD137. This subpopulation of de novo arising human CD137 + CD8 + T cells displayed a highly proliferative, fully activated effector and exhausted-like phenotype with enhanced expression of activation and exhaustion markers like PD-1, CD39, CD160, TIM-3, TIGIT and TOX, the senescence marker CD57 ( B3GAT1 ) and cytolytic effector molecules such as PRF1 , GZMH and NKG7 . Moreover, these CD137 + CD8 + T cells exhibited tumor-specific clonal expansion and presented signature overlap with tumor-reactive CD8 + T cells described in human cancer. We demonstrate superior anticancer activity of this exhausted-like human CD8 + T cell subset by adoptive transfer experiments using recipients bearing autologous human tumors. Mice adoptively transferred with CD137 + CD8 + T cells showed reduced tumor growth and higher CD8 + T cell tumor infiltration, correlating with control of human tumors. Interpretation We established an immunocompetent humanized tumor model, providing a tool for immunotherapy research and defined effective anticancer activity of human effector CD8 + T cells with an exhausted-like phenotype, supporting clinical exploration of such cells in adoptive T cell therapies. Funding Swiss Cancer Research foundation. Research in context Evidence before this study Antitumor immune responses and outcome of immunotherapeutic interventions are not always consistent between mouse models of cancer and data available in humans. This may be due to species-specific differences, therefore models with a potential for better translatability are needed, such as humanized mouse models. However, there is limited data on human antitumor T cell immunity in humanized mice. Added value of this study In this study, we established an immunocompetent humanized tumor model that recapitulates hallmarks of human antitumor T cell responses, offering the possibility for further translational investigation of the interface between human tumors and endogenous anticancer immunity. Furthermore, using functional in vitro assays and adoptive transfer, our study demonstrates the key importance of human effector CD8 + T cells with an activated and exhausted-like phenotype in the antitumor immune response. Implications of all the available evidence The autologous humanized tumor model provided in this study can serve as a tool to elucidate human-specific immune features. By bridging a gap between syngeneic mouse tumor models and human-specific antitumor immune responses, the model may help open up avenues for greater translatability of preclinical data. Our findings suggest that exhausted-like effector CD8 + T cells can be harnessed for clinical development of adoptive T cell therapies.

Systemic lupus erythematosus (SLE) is an autoimmune disease with significant morbidity and mortality. Type I interferon (IFN) drives SLE pathology and plasmacytoid dendritic cells (pDCs) are potent producers of IFN; however, the specific effects of pDC depletion have not been demonstrated. We show CD123 was highly expressed on pDCs and the anti-CD123 antibody CSL362 potently depleted pDCs in vitro. CSL362 pre-treatment abrogated the induction of IFNα and IFN-induced gene transcription following stimulation with SLE patient-derived serum or immune complexes. RNA transcripts induced in pDCs by ex vivo stimulation with TLR ligands were reflected in gene expression profiles of SLE blood, and correlated with disease severity. TLR ligand-induced protein production by SLE patient peripheral mononuclear cells was abrogated by CSL362 pre-treatment including proteins over expressed in SLE patient serum. These findings implicate pDCs as key drivers in the cellular activation and production of soluble factors seen in SLE.
© 2023 The Authors.

Advances in the understanding of the tumor microenvironment have led to development of immunotherapeutic strategies, such as chimeric antigen receptor T cells (CAR-Ts). However, despite success in blood malignancies, CAR-T therapies in solid tumors have been hampered by their restricted infiltration. Here, we used our understanding of early cytotoxic lymphocyte infiltration of human lymphocytes in solid tumors in vivo to investigate the receptors in normal, adjacent, and tumor tissues of primary non-small-cell lung cancer specimens. We found that CX3CL1-CX3CR1 reduction restricts cytotoxic cells from the solid-tumor bed, contributing to tumor escape. Based on this, we designed a CAR-T construct using the well-established natural killer group 2, member D (NKG2D) CAR-T expression together with overexpression of CX3CR1 to promote their infiltration. These CAR-Ts infiltrate tumors at higher rates than control-activated T cells or IL-15-overexpressing NKG2D CAR-Ts. This construct also had similar functionality in a liver-cancer model, demonstrating potential efficacy in other solid malignancies.
© 2023 The Author(s).