Immunology
Abstract
We conceived of a type of antitumor mechanism of action by which a soluble target in the tumor microenvironment, such as a tumor-driving growth factor, can be phagocytized along with cancer cells via antibody-dependent cellular phagocytosis (ADCP) using an antibody bispecific for the soluble target and a solid target overexpressed on the cancer cell surface. We explored this concept through engineering bispecific antibodies (BsAbs) co-targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor A (VEGFA) in an scFv-IgG format (VHS). We showed that the HER2-VEGFA BsAbs but not the parental antibodies alone or in combination induced co-phagocytosis of VEGFA and HER2-overexpressing cancer cells by tumor-associated macrophages via ADCP. In both immunocompromised and immunocompetent mice with aggressive tumors, the BsAbs demonstrated greater anti-metastasis activity and produced a greater survival benefit than the parental antibodies alone or in combination, in a manner dependent on Fcγ receptors on the macrophages. Our results provide proof of the concept that HER2-VEGFA BsAbs achieve enhanced antitumor activity by leveraging HER2 overexpressed on the cancer cell surface to induce co-phagocytosis of VEGFA. Our findings warrant clinical testing of the strategy to treat metastasis and recurrence of HER2-overexpressing solid tumors that respond to anti-VEGFA therapy.
Authors
Yang Lu, Songbo Qiu, Zhen Fan
Abstract
BACKGROUND. Understanding age-associated differences in acute and memory adaptive immunity to SARS-CoV-2 and how this contributes to more favorable outcomes in children is critically important. METHODS. We evaluated SARS-CoV-2–specific T cell, B cell, and antibody responses in 329 peripheral blood samples collected from non-hospitalized children, adolescents, and adults at three timepoints, including acute and memory timepoints. RESULTS. Most children produced robust CD4+ T cell responses during infection and developed memory CD4+ T cells; however, young children <4 years old often had undetectable CD4+ T cell responses compared to older children and adults. Young children also generated reduced frequencies of memory B cells; despite this, they mounted substantial and durable neutralizing antibody responses. CD4+ T cell responses in children were biased towards non-spike epitopes, especially in asymptomatic cases. Memory B cells in children were preferentially classical memory or, paradoxically, CXCR3+. CONCLUSION. These findings support the concept that the kinetics and composition of T and B cell responses shift across age groups and may be associated with milder COVID-19 outcomes in children.
Authors
L. Benjamin Hills, Numana Bhat, Jillian H. Hurst, Amber Myers, Thomas W. Burke, Micah T. McClain, Elizabeth Petzold, Alexandre T. Rotta, Nicholas A. Turner, Alba Grifoni, Daniela Weiskopf, Yvonne Dogariu, Genevieve G. Fouda, Sallie R. Permar, Alessandro Sette, Christopher W. Woods, Matthew S. Kelly, Shane Crotty
Abstract
Recent findings suggest that the small intestine (SI) is a novel site for B cell lymphopoiesis during fetal and neonatal life. However, the unique and/or conserved features that enable B cell development at this site remain unclear. To investigate the molecular and cellular scaffolds for B cell lymphopoiesis in mouse and human fetal intestines we leveraged single-cell RNA sequencing, in situ immunofluorescence, spatial transcriptomics and high-dimensional spectral flow cytometry. We found that SI mesenchymal and stromal cells expressed higher levels of chemokines known to recruit common lymphoid progenitors. Importantly, local lymphatic endothelial cells expressed IL7 and TSLP in proximity to IL7R+ precursor B cells, likely promoting their differentiation in the SI. Notably, we found that fetal-derived lymphoid tissue inducer (LTi) cells were required for B cell development and localization in the SI, but not fetal liver. These findings identify a lymphoid tissue development-independent role for this immune cell in B cell development. Collectively, our data reveal a conserved intestinal B cell niche in mice and humans, challenging traditional models of lymphopoiesis. The identification of a requisite cellular/molecular scaffold for fetal B cell development allows future studies to test the importance of this de novo B cell lymphopoiesis to long-term immunity.
Authors
Kimberly A. Carroll, Weihong Gu, Long Phan, Eduardo Gonzalez Santiago, Wenjia Wang, George C. Tseng, Liza Konnikova, Shruti Sharma
Abstract
Recurrent acute anterior uveitis is a frequent extra-articular manifestation of the axial spondyloarthropathies (AxSpA); chronic inflammatory diseases affecting the spine, enthesis, peripheral joints, skin, and gastrointestinal tract. Pathology in AxSpA has been associated with local tissue-resident populations of interleukin (IL)-23 responsive lymphoid cells. Here we characterize a population of ocular T cell defined by CD3+CD4-CD8-CD69+gdTCR+IL-23R+ that reside within the anterior uvea as an ocular entheseal analogue of the mouse eye. Localised cytokine expression demonstrates that uveal IL-23R+ IL-17A-producing cells are both necessary and sufficient to drive uveitis in response to IL-23. This T cell population is also present in humans, occupying extravascular tissues of the anterior uveal compartment. Consistent with the concept of IL-23 as a unifying mediator in AxSpA, we present evidence that IL-23 can also act locally on tissue resident T cells in the anterior compartment of the eye at sites analogous to the enthesis to drive ocular inflammation.
Authors
Robert Hedley, Amy Ward, Colin J. Chu, Sarah E. Coupland, Serafim Kiriakidis, Peter C. Taylor, Stephanie G. Dakin, ORBIT Research Consortium, Christopher D. Buckley, Jonathan Sherlock, Andrew D. Dick, David A. Copland
Abstract
BK virus nephropathy is a severe, graft-threatening complication of kidney transplantation that requires an effective T cell response. It typically emerges in the kidney medulla. Elevated osmolyte concentrations that dynamically respond to loop diuretic therapy characterize this environment. BK-viremia development in kidney graft recipients negatively correlated with loop diuretic therapy. The association remained significant in multivariable and propensity score matched analyses. Kidney function was better preserved and CD8+ T cell abundance higher in loop diuretic-exposed allografts. CD8+ T cell densities in healthy human and murine kidney medulla were lower than in cortex and increased upon loop diuretic therapy in mice. As a potential underlying mechanism, kidney medullary NaCl and urea concentrations decreased primary human CD8+ T cell numbers in vitro by induction of cell death and limitation of proliferation, respectively. Both osmolytes downregulated interferon-related gene expression. NaCl induced p53-dependent apoptosis and upregulated Na+-transporter SLC38A2, which promoted caspase 3 activation. Both decreased T cell response and cytokine secretion in response to viral peptide and allogenic tubular epithelial cell killing, components of anti-BKV response in the kidney allograft. Our results propose osmolyte-mediated mitigation of CD8+ T cell function as a what we believe to be novel mechanism that impairs immune response to BK virus, therapeutic potential of which is testable.
Authors
Peyman Falahat, Adrian Goldspink, Lucia Oehler, Jessica Schmitz, Julia Miranda, Islem Gammoudi, Jan Hinrich Bräsen, Niklas Klümper, Olena Babyak, Christian Kurts, Herrmann Haller, Marieta Toma, Sibylle von Vietinghoff
Abstract
We assessed the therapeutic efficacy of a semiallogeneic dendritic cell (DC) vaccine in comparison to a syngeneic one for suppression of B16-F10 and TC-1 tumors. Syngeneic bone marrow–derived DCs (BMDCs) were generated from C57BL/6J mice and semiallogeneic BMDCs with a mutation in either MHC class I or II were generated from B6.C-H2-Kbm1/ByJ or B6(C)-H2-Ab1bm12/KhEgJ mice, respectively. We demonstrated in vivo and in vitro that the MHC class II semiallogeneic BMDC vaccine had superior efficacy over the syngeneic and the MHC class I semiallogeneic BMDC vaccine, providing allogeneic CD4+ T cell help to enhance the antitumor CD8+ T cell response through allogeneic stimulation by the mutant MHC class II molecules. We discovered that this help was induced only at an early stage of tumor growth and at a later stage of tumor growth; combining our BMDC vaccine with Treg depletion enhanced tumor suppression. We demonstrated the improved efficacy of a semiallogeneic BMDC vaccine that kept tumor-peptide presentation intact on syngeneic MHC class I molecules so that mutant MHC class II could provide allogeneic help. This strategy should enable promising new DC-based cancer immunotherapies, offering an alternative to autologous DC vaccines by incorporating allogenicity as an adjuvant.
Authors
Noriko Seishima, William Becker, Purevdorj B. Olkhanud, Hoyoung M. Maeng, Miguel A. Lopez-Lago, William V. Williams, Jay A. Berzofsky
Abstract
While the accumulation of tumor-associated macrophages (TAMs) in glioblastoma (GBM) has been well documented, targeting TAMs has thus far yielded limited clinical success in slowing GBM progression due, in part, to an incomplete understanding of TAM function. Using an engineered 3D hydrogel–based model of the brain tumor microenvironment (TME), we show that M2-polarized macrophages stimulate transcriptional and phenotypic changes in GBM stem cells (GSCs) closely associated with the highly aggressive and invasive mesenchymal subtype. By combining proteomics with GBM patient single-cell transcriptomics, we identify multiple TAM-secreted proteins with putative proinvasive functions and validate TGF-β induced (TGFBI, also known as BIGH3) as a targetable TAM-secreted tumorigenic factor. Our work highlights the utility of coupling multiomics analyses with engineered TME models to investigate TAM–cancer cell crosstalk and offers insights into TAM function to guide TAM-targeting therapies.
Authors
Erin A. Akins, Dana Wilkins, Zaki Abou-Mrad, Kelsey Hopland, Robert C. Osorio, Kenny K.H. Yu, Manish K. Aghi, Sanjay Kumar
Abstract
T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and oxidative phosphorylation. Both groups had improved primary and memory recall responses following infection with murine gammaherpesvirus-68. However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, CD8+ T cell populations after B cell lymphoma challenge were smaller in both groups, resulting in poorer protection, which was rescued by glutamine and acetate supplementation. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.
Authors
Taewook Kang, Young-Kwang Usherwood, Julie A. Reisz, Sukrut C. Kamerkar, Rachel Culp-Hill, Owen M. Wilkins, Andreia F. Verissimo, Fred W. Kolling IV, Anton M. Hung, Shawn C. Musial, Pamela C. Rosato, Angelo D’Alessandro, Henry N. Higgs, Edward J. Usherwood
Abstract
Authors
Joshua A. Keefe, Jose Alberto Navarro-Garcia, Shuai Zhao, Mihail G. Chelu, Xander H.T. Wehrens
Abstract
Radiotherapy triggers chemokine release and leukocyte infiltration in pre-clinical models through activation of the senescence-associated secretory phenotype (SASP). However, effects of irradiation on senescence and SASP in human tissue and in the context of particle radiotherapy remain unclear. Here, we analyzed chemokine patterns after radiotherapy of human pancreatic tumors and cancer cell lines. We show that irradiated tumor cells co-express SASP chemokines in defined modules. These chemokine modules correlated with infiltration of distinct leukocyte subtypes expressing cognate receptors. We developed a patient-derived pancreatic tumor explant system, which confirmed our identified radiation-induced chemokine modules. Chemokine modules were partially conserved in cancer cells in response to photon and particle irradiation showing a dose-dependent plateau effect and induced subsequent migration of NK and T cell populations. Hence, our work reveals redundant interactions of cancer cells and immune cells in human tissue, suggesting that targeting multiple chemokines is required to efficiently perturb leukocyte infiltration after photon or particle radiotherapy.
Authors
Joscha A. Kraske, Michael M. Allers, Aleksei Smirnov, Bénédicte Lenoir, Azaz Ahmed, Meggy Suarez-Carmona, Mareike Hampel, Damir Krunic, Alexandra Tietz-Dalfuß, Tizian Beikert, Jonathan M. Schneeweiss, Stephan Brons, Dorothee Albrecht, Thuy Trinh, Muzi Liu, Nathalia A. Giese, Christin Glowa, Jakob Liermann, Ramon Lopez Perez, Dirk Jäger, Jürgen Debus, Niels Halama, Peter E. Huber, Thomas Walle
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