The majority of HIV-1 elite controllers (EC) restrict HIV-1 replication through highly functional HIV-1-specific T cell responses, but mechanisms supporting the evolution of effective HIV-1-specific T cell immunity in these patients remain undefined. Cytosolic immune recognition of HIV-1 in conventional dendritic cells (cDC) can facilitate priming and expansion of HIV-1-specific T cells; however, HIV-1 seems to be able to avoid intracellular immune recognition in cDCs in most infected individuals. Here, we show that exposure of cDCs from EC to HIV-1 leads to a rapid and sustained production of type I interferons and upregulation of several interferon-stimulated effector genes. Emergence of these cell-intrinsic immune responses was associated with a reduced induction of SAMHD1 and LEDGF/p75, and an accumulation of viral reverse transcripts, but inhibited by pharmacological blockade of viral reverse transcription or siRNA-mediated silencing of the cytosolic DNA sensor cGAS. Importantly, improved cell-intrinsic immune recognition of HIV-1 in cDCs from elite controllers translated into stronger abilities to stimulate and expand HIV-1-specific CD8 T cell responses. These data suggest an important role of cell-intrinsic type I interferon secretion in dendritic cells for the induction of effective HIV-1-specific CD8 T cells, and may be helpful for eliciting functional T cell immunity against HIV-1 for preventative or therapeutic clinical purposes.
Purpose The solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models. Experimental design We evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo. Results Cell surface expression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions. Conclusions Together, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).
PurposeThe solid tumor microenvironment (TME) drives T cell dysfunction and inhibits the effectiveness of immunotherapies such as chimeric antigen receptor-based T cell (CAR T) cells. Early data has shown that modulation of T cell metabolism can improve intratumoral T cell function in preclinical models.Experimental DesignWe evaluated GPC3 expression in human normal and tumor tissue specimens. We developed and evaluated BOXR1030, a novel CAR T therapeutic co-expressing glypican-3 (GPC3)-targeted CAR and exogenous glutamic-oxaloacetic transaminase 2 (GOT2) in terms of CAR T cell function both in vitro and in vivo.ResultsExpression of tumor antigen GPC3 was observed by immunohistochemical staining in tumor biopsies from hepatocellular carcinoma, liposarcoma, squamous lung cancer, and Merkel cell carcinoma patients. Compared to control GPC3 CAR alone, BOXR1030 (GPC3-targeted CAR T cell that co-expressed GOT2) demonstrated superior in vivo efficacy in aggressive solid tumor xenograft models, and showed favorable attributes in vitro including an enhanced cytokine production profile, a less-differentiated T cell phenotype with lower expression of stress and exhaustion markers, an enhanced metabolic profile and increased proliferation in TME-like conditions.ConclusionsTogether, these results demonstrated that co-expression of GOT2 can substantially improve the overall antitumor activity of CAR T cells by inducing broad changes in cellular function and phenotype. These data show that BOXR1030 is an attractive approach to targeting select solid tumors. To this end, BOXR1030 will be explored in the clinic to assess safety, dose-finding, and preliminary efficacy (NCT05120271).Statement of Translational RelevanceChimeric antigen receptor-based T cell (CAR T) therapeutics have revolutionized the field of oncology. Despite early successes targeting hematological malignancies, substantial challenges limit application of CAR T therapy in solid tumors, in part due to the suppressive tumor microenvironment which drives T cell exhaustion and metabolic dysfunction. Glutamic-oxaloacetic transaminase 2 (GOT2) is a mitochondrial enzyme in glutamine metabolism and contributes to cellular redox balance.Glypican-3 (GPC3) is an oncofetal tumor antigen with restricted expression on normal tissues and high prevalence in several solid tumors. We describe BOXR1030, a novel CAR T therapeutic co-expressing GPC3-targeted CAR and exogenous GOT2. Compared to T cells expressing CAR alone, BOXR1030 T cells demonstrated superior in vivo efficacy and have favorable attributes including enhanced cytokine production, a less-differentiated phenotype with lower expression of exhaustion markers, and an enhanced metabolic profile. These data support BOXR1030 as a potential treatment to explore in select solid tumor indications.
Weevils (Coleoptera: Curculionoidea) represent a remarkable proportion of global biodiversity, yet studies addressing their biogeography remain scarce. The arid parts of sub-Saharan Africa harbour several interesting weevil lineages, the most spectacular being the larger flightless weevils such as the Microcerinae and Brachycerus. Here we map the species richness of these two groups to identify hotspots in their diversity, and make inferences regarding the factors that may have contributed to the observed patterns. Exceptional richness values in both groups are found in southern Africa, and more specifically in the Nama Karoo, which is unremarkable in terms of plant diversity. By comparisons, plant diversity hotspots such as the Succulent Karoo and the Cape Floristic Region appear to have high, but not exceptional, weevil richness. Species richness levels were also high in the grassland and savanna areas of south-eastern Africa, which are not arid. The representation of genera considered here and their closest relatives, suggest an African origin for both lineages. This, combined with recent insights into weevil evolution, raise the possibility that advanced weevils as a whole (the family Curculionidae) originated in Africa and that some of its earliest offshoots survived and subsequently diversified here thanks to multiple factors, relating to climate and plant diversity alike.
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