Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated Type 1 effectors within the tumor micro-environment
Immunity 2026
Maltez VI, Arora C, Gribbin KP, Caruso B, Haerr ME, Sor R, Lian Q, Blise KE, Sivagnanam S, Sears RC , Coussens LM, Vonderheide RH, Germain RN, Byrne KT Highlights •Agonistic 𝛼CD40 reduced tumor Treg cells via loss of Foxp3 to generate “ExTreg” cells •ExTreg cells required DCs and IL-12/IFN-γ and accumulated with DCs at the tumor border •ExTreg cells acquired Tbet and Ifng expression aligned with anti-tumor effector T cells •Nuclear NFAT1 revealed increased antigen reactivity among ExTreg cells after 𝛼CD40
Lamborn IT, Ichise H, Speranza E, Arakkal L, Maltez VI, Yaniv Z, Radtke AJ, Germain RN Iterative bleaching extends multiplexity (IBEX) is an easy-to-use, highly multiplex immunofluorescent tissue imaging method that employs widely available microscopy platforms, commercial reagents, and open-source software. In this article, we describe how to implement this method in a laboratory that has minimal experience with immunohistochemistry.
Yaniv Z, Anidi IU, Arakkal L, Arroyo-Mejías AJ, Beuschel RT, Börner K, Chu CJ, Clark BH, Clatworthy MR, Colautti J, Coscia F, Croteau J, Denha S, Dever R, Dutra WO, Fritzsche S, Fullam S, Gerner MY, Gola A, Gollob KJ, Hernandez JM, Hor JL, Ichise H, Jing Z, Jonigk D, Kandov E, Kastenmüller W, Koenig JFE, Kothurkar A, Kortekaas RK, Kreins AY, Lamborn IT, Lin Y, Luciano Pereira Morais K, Lunich A, Luz JCS, MacDonald RB, Makranz C, Maltez VI, McDonough JE, Moriarty RV, Ocampo-Godinez JM, Murakami Olyntho V, Oxenius A, Padhan K, Remmert K, Richoz N, Schrom EC, Shang W, Shi L, Shih RM, Speranza E, Stierli S, Teichmann SA, Verse TZ, Vierhout M, Wachter BT, Wade-Vallance AK, Williams M, Zangger N, Germain RN, Radtke AJ
Khalil DN, Gomez R, Regev A, Samaan F, Marouf Y, Budhu S, Hirschhorn D, Schulze I, Lavery JA, Ceglia N, Freeman SS, Maltez VI, Garcia JM, Suek N, Weng CH, Cabanski CR, Monette S, Romin Y, Li Y, Chaligne R, Yellin MJ, Keler T, Maurer DM, Flamar AL, Morgado-Palacin L, Mangarin LM, Harding JJ, Park W, Lyman JP, Maddock S, O'Hara MH, Abou-Alfa GK, Vonderheide RH, O'Reilly EM, Germain RN, Wolchok JD, Merghoub T Although the role of neutrophils in modulating antitumor T-cell responses has been extensively studied, their direct effects on tumor cells remain less well understood. In this study, we investigated whether neutrophils have the capacity to directly kill tumor cells independently of T cells. We found that anti-CD40-based therapy, when combined with IL10 receptor blockade, initiates a Batf3-dependent pathway in which IL12 and IFNγ secretion results in oncolytic neutrophil activity. Using a combination of microscopy, single-cell, and functional assays, we observed that killing of tumor cells by neutrophils is dependent on physical contact and degranulation. This degranulation-mediated killing is associated with an atypical dynamic invasive neutrophil phenotype. In line with our preclinical findings, our phase I trial of anti-CD40 shows that circulating IL12, IFNγ, and IL10 increase in response to anti-CD40, whereas our phase Ib/2 PRINCE study shows that lower circulating IL10 is associated with favorable overall survival (OS) specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony-stimulating factor is associated with improved OS, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.
Radtke AJ, Anidi IU, Arakkal L, Arroyo-Mejias AJ, Beuschel RT, Börner K, Chu CJ, Clark B, Clatworthy MR, Colautti J, Coscia F, Croteau J, Denha S, Dever R, Dutra WO, Fritzsche S, Fullam S, Gerner MY, Gola A, Gollob KJ, Hernandez JM, Hor JL, Ichise H, Jing Z, Jonigk D, Kandov E, Kastenmüller W, Koenig JFE, Kortekaas RK, Kothurkar A, Kreins AY, Lamborn IT, Lin Y, Luciano Pereira Morais K, Lunich A, Luz JCS, MacDonald RB, Makranz C, Maltez VI, McDonough JE, Moriarty RV, Ocampo-Godinez JM, Olyntho VM, Oxenius A, Padhan K, Remmert K, Richoz N, Schrom EC, Shang W, Shi L, Shih RM, Speranza E, Stierli S, Teichmann SA, Veres TZ, Vierhout M, Wachter BT, Wade-Vallance AK, Williams M, Zangger N, Germain RN, Yaniv Z Multiplexed imaging is a powerful approach in spatial biology, although it is complex, expensive and labor-intensive. Here, we present the IBEX Knowledge-Base, a central resource for reagents, protocols and more, to enhance knowledge sharing, optimization and innovation of spatial proteomics techniques.
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. 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 Granulomas often form around pathogens that cause chronic infections. Here, we discover an innate granuloma model in mice with an environmental bacterium called Chromobacterium violaceum.
Maltez VI*, Nozaki K*, 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.