IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer

Lunardi, Serena; Lim, Su Yin; Muschel, Ruth J.; Brunner, Thomas

doi:10.1080/2162402x.2015.1027473

Cited by 76 publications

(65 citation statements)

References 10 publications

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“…We speculate that LDH-A deletion may favor production of IL-17 by ‘regulatory’ IL-10 producing cells. Further, IP-10/CXCL10 is highly expressed by PSCs in the presence of pancreatic cancer cells (PCCs) and its expression correlates with infiltration by regulatory T cells (Tregs) and poor survival (30,31). …”

Section: Discussionmentioning

confidence: 99%

Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity

et al. 2017

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Immunometabolism is emerging as a critical determinant of cancer pathophysiology. In this study, we explored the contributions of macrophage-expressed lactate dehydrogenase-A (LDH-A) to tumor formation in a K-Ras murine model of lung carcinoma. Myeloid-specific deletion of LDH-A promoted accumulation of macrophages with a CD86high and MCP-1high M1-like phenotype that suppressed tumor growth. This phenotypic effect was accompanied by reduced VEGF expression and angiogenesis; diminished numbers of PD-L1+ cancer cells; increased numbers of CD3+ T cells and activation status of CD8+ T cells. Further, it was associated with more pronounced antitumor T cell immunity via induction of IL-17 and IFNγ-producing CD8+ T (Tc17 and Tc1) cells, likely via suppression of lactate-driven PD-L1 expression. Our results suggest that expression of LDH-A and lactate by macrophage in the tumor microenvironment are major drivers of T cell immunosuppression, strongly supporting the concept of targeting stromal LDH-A as an effective strategy to blunt tumoral immune escape.

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Section: Discussionmentioning

confidence: 99%

Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity

et al. 2017

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“…The latter observation highlights the variable actions reported for CXCL10, since, depending upon the pathogen, model, and organ examined (53), CXCL10 deletion or neutralization can have no effect on (54, 55), reduce (51,52,56), or apparently even enhance (57, 58) host resistance to infection. CXCL10 also influences and recruits suppressive CXCR3 ϩ regulatory T cells to the tissues (59,60), and the absence of CXCR3 ϩ regulatory T cells might enhance the control of L. donovani replication in CXCL10 Ϫ/Ϫ mice. That said, however, it is not clear why early-stage infection was better controlled in CXCL10 Ϫ/Ϫ mice than CXCR3 Ϫ/Ϫ mice, although mice of both backgrounds showed similarly deficient initial mononuclear cell recruitment.…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

et al. 2017

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In the livers of C57BL/6 mice, gamma interferon (IFN-␥) controls intracellular Leishmania donovani infection and the efficacy of antimony (Sb) chemotherapy. Since both responses usually correlate with granulomatous inflammation, we tested six prominently expressed, IFN-␥-regulated chemokines-CXCL9, CXCL10, CXCL13, CXCL16, CCL2, and CCL5-for their roles in (i) mononuclear cell recruitment and granuloma assembly and maturation, (ii) initial control of infection and self-cure, and (iii) responsiveness to Sb treatment. Together, the results for the L. donovani-infected livers of chemokine-deficient mice (CXCR6 Ϫ/Ϫ mice were used as CXCL16-deficient surrogates) indicated that individual IFN-␥-induced chemokines have diverse affects and (i) may be entirely dispensable (CXCL13, CXCL16), (ii) may promote (CXCL10, CCL2, CCL5) or downregulate (CXCL9) initial granuloma assembly, (iii) may enhance (CCL2, CCL5) or hinder (CXCL10) early parasite control, (iv) may promote granuloma maturation (CCL2, CCL5), (v) may exert a granuloma-independent action that enables self-cure (CCL5), and (vi) may have no role in responsiveness to chemotherapy. Despite the near absence of tissue inflammation in early-stage infection, parasite replication could be controlled (in CXCL10 Ϫ/Ϫ mice) and Sb was fully active (in CXCL10 Ϫ/Ϫ , CCL2 Ϫ/Ϫ , and CCL5 Ϫ/Ϫ mice). These results characterize chemokine action in the response to L. donovani and also reemphasize that (i) recruited mononuclear cells and granulomas are not required to control infection or respond to Sb chemotherapy, (ii) granuloma assembly, control of infection, and Sb's efficacy are not invariably linked expressions of the same T cell-dependent, cytokine-mediated antileishmanial mechanism, and (iii) granulomas are not necessarily hallmarks of protective antileishmanial immunity.KEYWORDS chemokines, visceral leishmaniasis, Leishmania donovani, granuloma, pentavalent antimony I n visceral leishmaniasis, a disseminated protozoal infection, tissue macrophages in the liver, spleen, and bone marrow are targeted and support intracellular parasite replication. In the susceptible host, experimental Leishmania donovani infection in the liver does not come under control nor are parasites killed until either chemotherapy is given or T cell-dependent, multi-cytokine-driven mechanisms emerge and macrophage activation is induced. In the livers of infected wild-type (WT) C57BL/6 (B6) and BALB/c mice, this immunoinflammatory response is usually associated with mononuclear cell recruitment to and granuloma assembly at parasitized Kupffer cells (1-8). In the granulomatous environment, this T cell-and cytokine-mediated response also directs self-cure in initially susceptible B6 and BALB/c mice and, in addition, regulates the intracellular efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (2, 4, 6, 7, 9-11).

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“…Overall, 35/42 (83.3%) participants who received BMS-986184 in the SAD study and 8/12 (66.7%) participants who received BMS-986184 in the MAD study completed the study period. The main reasons for not (4,4) 0.492 18.6 0.313-0.671 ω 2 K a (5,5) 0.181 58.2 0-0.387 ω 2 K in (6,6) 0.117 30.1 0.048-0.186 ω 2 K deg (7,7) 0.031 354.3 0-0.249 ω 2 K int (8,8) 0.034 120.3 0-0.115 ω 2 K SS (9,9) 3.181 58.0 0-6.794 ω 2 F1 (10,10) 0.260 139.6 0-0.97 ω 2 E M AX (11,11) 0.347 170. completing the study were withdrawal of consent (3/54; 5.6%) and adverse events (AEs; 3/54; 5.6%). Baseline characteristics for both the SAD and MAD cohorts are shown in Table 1.…”

Section: Study Populationmentioning

confidence: 99%

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon‐γ–Induced Protein 10, BMS‐986184, in Healthy Participants to Guide Therapeutic Dosing

Cai

Leil

Gibiansky³

et al. 2020

Clinical Pharm in Drug Dev

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BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials.Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Additional supplemental information can be found by clicking the Supplements link in the PDF toolbar or the Supplemental Information section at the end of webbased version of this article.

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IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer

Cited by 76 publications

References 10 publications

Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity

Deletion of Lactate Dehydrogenase-A in Myeloid Cells Triggers Antitumor Immunity

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon‐γ–Induced Protein 10, BMS‐986184, in Healthy Participants to Guide Therapeutic Dosing

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