Highlights d CD40L + CAR T cells kill antigen-negative tumor cells through CD40/CD40L interactions d CD40L + CAR T cells improve antitumor response compared with second-generation CAR T cells d CD40L + CAR T cells license APCs in vivo to aid in antitumor response d Licensed APCs prime non-CAR T cells to recognize tumor cells and produce cytokines
SUMMARY
Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrate that the clonal abundance of CD4+ T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor specific CD4+ T cell population. However, through clonally derived help, this population acquired a polyfunctional effector phenotype and antitumor immunity was enhanced. Conversely, development of effector function was attenuated at low precursor frequencies due to irreversible T cell exhaustion. Our findings assert that the differential effects of T cell clonal abundance on phenotypic outcome should be considered during the design of adoptive T cell therapies, including use of engineered T cells.
While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3−/− mice lacking the CD103+ conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b−CD103− double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8+ T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses.
While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many
others experience milder symptoms. We sought a holistic understanding of the
severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood
preserving single-cell analysis protocol to integrate contributions from all major cell
types including neutrophils, monocytes, platelets, lymphocytes and the contents of
serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated
gene (ISG) expression across every cell population and these cells are
systemically absent in patients with severe disease. Severe COVID-19 patients also
paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load
as compared to mild disease. Examination of the serum from severe patients
demonstrates that they uniquely produce antibodies with multiple patterns of specificity
against interferon-stimulated cells and that those antibodies functionally block the
production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected
antibody responses pit the immune system against itself in many COVID-19
patients and this defines targets for immunotherapies to allow immune systems to
provide viral defense.
While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
In this Article, in the Methods section 'Patients, participants, severity score and clinical data collection', the word 'mild-moderate' should be replaced by 'severe' in the sentence 'Patients classified as … (typically five days or more).'. The corrected sentence should read: 'Patients classified as having severe disease are patients who required intensive care and mechanical ventilation (typically five days or more).'. The Article has been corrected online.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.