Agonistic anti-CD40 converts Tregs into Type 1 effectors within the tumor micro-environment
BioRxiv 2023
Maltez VI, Arora C, Sor A, Lian Q, Vonderheide RH, Germain RN*, Byrne KT*
*contributed equally
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The mechanism of CD40-mediated Treg loss is poorly understood, as Tregs are CD40-negative. Here we have explored the mechanistic basis for the loss of Foxp3 T cells upon anti-CD40 treatment and find, using tissue-level multiplex immunostaining and orthogonal dissociated cell analyses, that Tregs are not depleted but converted into interferon-γ (IFN-γ) producing, Type I CD4+ T effector cells. This process depends on IL-12 and IFN-γ signaling evoked by action of the anti-CD40 antibody on dendritic cells (DCs), especially BATF3-dependent cDC1s. These findings provide insight into a previously unappreciated mechanism of CD40 agonism as a potent anti-tumor intervention that promotes the re-programming of Tregs into tumor-reactive CD4+ effector T cells, markedly augmenting the anti-tumor response.
Globig AM, Zhao S, Roginsky J, Maltez VI, Guiza J, Avina-Ochoa N, Heeg M, Araujo Hoffmann F, Chaudhary O, Wang J, Senturk G, Chen D, O'Connor C, Pfaff S, Germain RN, Schalper KA, Emu B, Kaech SM.
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CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of T cell exhaustion through the β1-adrenergic receptor ADRB1. Here, we uncover a new mechanism by which blocking β-adrenergic signalling in CD8+ T cells rejuvenates anti-tumour functions.
An innate granuloma eradicates an environmental pathogen using Gsdmd and Nos2
Nature Communications 2023
Harvest CK, Abele TJ, Yu C, Beatty CJ, Amason ME, Billman ZP, DePrizio MA, Souza FW, Lacey CA, Maltez VI, Larson HN, McGlaughon BD, Saban DR, Montgomery SA, and Miao EA
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Granulomas often form around pathogens that cause chronic infections. Here,
we discover an innate granuloma model in mice with an environmental bac-
terium called Chromobacterium violaceum.
Nozaki K*, Maltez VI*, Rayamajhi M, Tubbs AL, Mitchell JE, Lacey CA, Harvest CK, Li L, Nash WT, Larson HN, McGlaughon BD, Moorman NJ, Brown MG, Whitmire JK, Miao EA
*contributed equally
Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons. We show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.
Kovacs SB, Oh C, Maltez VI, McGlaughon BD, Verma A, Miao EA, Aachoui Y.
Either caspase-1 or caspase-11 can cleave gasdermin D to cause pyroptosis, eliminating intracellular replication niches. We previously showed that macrophages detect Burkholderia thailandensis via NLRC4, triggering the release of interleukin (IL)-18 and driving an essential interferon (IFN)-γ response that primes caspase-11. We present an example of inflammasome sensors causing diverging outcomes in different cell types. Thus, cell fates are dictated not simply by the pathogen or inflammasome, but also by how the cell is wired to respond to detection events.
Alspach E, Chow RD, Demehri S, Guerriero JL, Gujar S, Hartmann FJ, Helmink BA, Hudson WH, Ho WJ, Ma L, Maier BB, Maltez VI, Miller BC, Moran AE, Parry EM, Pillai PS, Rafiq S, Reina-Campos M, Rosato PC, Rudqvist NP, Ruhland MK, Sagiv-Barfi I, Sahu AD, Samstein RM, Schürch CM, Sen DR, Thommen DS, Wolf Y, Zappasodi R..
*all authors contributed equally
Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field. This commentary outlines the lessons that emerged from the inaugural symposium highlighting the areas of scientific and career development that are essential for professional growth in the field of cancer immunology and beyond. Leading scientists and clinicians in the field provided their experience on the topics of scientific trajectory, career trajectory, publishing, fundraising, leadership, mentoring, and collaboration. Herein, we provide a conceptual and practical framework for career development to the broader scientific community.
Maltez VI, Tubbs AL, Cook KD, Aachoui Y, Falcone EL, Holland SM, Whitmire JK, Miao EA.
Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens.
A phenotype at last: essential role for the Yersinia enterocolitica Ysa type III secretion system in a Drosophila melanogaster S2 cell model
Infection and Immunity 2013
Walker KA, Maltez VI, Hall JD, Vitko NP, Miller VL
The highly pathogenic Yersinia enterocolitica strains have a chromosomally encoded type III secretion system (T3SS) that is expressed and functional in vitro only when the bacteria are cultured at 26 °C. Mutations that render this system nonfunctional are slightly attenuated in the mouse model of infection only following an oral inoculation and only at early time points postinfection. The discrepancy between the temperature required for the Ysa gene expression and the physiological temperature required for mammalian model systems has made defining the role of this T3SS challenging. Importantly, we show that the Ysa T3SS is required for robust intracellular replication. A secretion-deficient mutant lacking the secretin gene, ysaC, is defective in replication within S2 cells, marking the first demonstration of a pronounced Ysa-dependent virulence phenotype.