Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy

Hutchison, Shana; Sahay, Bikash; Mello, Souza Ch de; Sayour, EJ; Lejeune, Amandine; Szivek, Anna; Livaccari, AM; Fox-Alvarez, Stacey A.; Salute, Marc E.; Powers, Lindsay; Milner, Robert J.

doi:10.1016/j.vetimm.2019.109912

Cited by 18 publications

(24 citation statements)

References 73 publications

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“…Serum PGE 2 , IL-12p40, IL-8, MCP-1, and SCF concentrations were higher in dogs with OMM than healthy controls, providing clues to the immunological changes associated with tumorigenesis and progression of OMM, including resistance to endogenous antitumor mechanisms. These findings are consistent with previous reports showing elevated serum IL-12p40 in osteosarcoma 42 , IL-8 in mammary tumor and osteosarcoma 42 – 44 , and MCP-1 in lymphoma, histiocytic sarcoma, urothelial carcinoma, and malignant melanoma 45 – 49 compared to healthy dogs. Upregulation of these factors may reflect immunological responses in the tumor microenvironment, but the cellular and locoregional sources of these factors remain to be investigated.…”

Section: Discussionsupporting

confidence: 93%

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

Maekawa

Konnai

Asano

et al. 2022

Sci Rep

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Immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies are widely used to treat human cancers, and growing evidence suggests that ICIs are promising treatments for canine malignancies. However, only some canine oral malignant melanoma (OMM) cases respond to ICIs. To explore biomarkers predictive of survival in dogs with pulmonary metastatic OMM receiving the anti-PD-L1 antibody c4G12 (n = 27), serum concentrations of prostaglandin E2 (PGE2), cytokines, chemokines, and growth factors were measured prior to treatment initiation. Among 12 factors tested, PGE2, interleukin (IL)-12p40, IL-8, monocyte chemotactic protein-1 (MCP-1), and stem cell factor (SCF) were higher in OMM dogs compared to healthy dogs (n = 8). Further, lower baseline serum PGE2, MCP-1, and vascular endothelial growth factor (VEGF)-A concentrations as well as higher IL-2, IL-12, and SCF concentrations predicted prolonged overall survival. These observations suggest that PGE2 confers resistance against anti-PD-L1 therapy through immunosuppression and thus is a candidate target for combination therapy. Indeed, PGE2 suppressed IL-2 and interferon (IFN)-γ production by stimulated canine peripheral blood mononuclear cells (PBMCs), while inhibition of PGE2 biosynthesis using the COX-2 inhibitor meloxicam in combination with c4G12 enhanced Th1 cytokine production by PBMCs. Thus, serum PGE2 may be predictive of c4G12 treatment response, and concomitant use of COX-2 inhibitors may enhance ICI antitumor efficacy.

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Section: Discussionsupporting

confidence: 93%

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

Maekawa

Konnai

Asano

et al. 2022

Sci Rep

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“…As G-CSF, GM-CSF, MCP-1, and TNFα are known to be important cytokines for recruitment of MDSCs [33][34][35], we then examined the recruitment of MDSCs in vivo. FACS analysis showed that, more G-MDSCs were recruited in mice injected with 1601 cells than those injected with 1601-ko-Ptges cells (8.0% vs 2.8% in WT mice; and 10.7% vs 6.4% in Gprc5a-ko mice), and more G-MDSCs were recruited in Gprc5a-ko mice than in C57-WT ones (10.7% vs 8.0% for 1601 cells; and 6.4% vs 2.8% for 1601-ko-Ptges cells) (Fig.…”

Section: Ptges/pge 2 -Mediated Recruitment Of Mdscs Is Essential For mentioning

confidence: 99%

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Wang

Jing

et al. 2020

Oncogene

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Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE 2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE 2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE 2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE 2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE 2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.

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“…Mucha et al reported an MDSC frequency of 18% in dogs with neoplasms with metastases, and 0.25% in healthy dogs ( 30 ). Other studies that characterized the subpopulations of (M)-MDSCs and (PMN)-MDSCs used different methodologies, such as different antibodies and types of samples, including whole blood or PMBCs, and found different proportions of these cell populations in the peripheral blood of dogs with cancer ( 45 , 46 ). As there are no standardized methodologies, we cannot compare the findings of the current study with those of previously published studies.…”

Section: Discussionmentioning

confidence: 99%

Association of Systemic Inflammatory and Immune Indices With Survival in Canine Patients With Oral Melanoma, Treated With Experimental Immunotherapy Alone or Experimental Immunotherapy Plus Metronomic Chemotherapy

Garcia

Nowosh

López³

et al. 2022

Front. Vet. Sci.

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Analysis of the expression of inflammatory markers before starting treatment in human patients with cancer helps to predict outcomes and prognosis; however, there have been few studies on this topic in veterinary medicine. The present study aimed to evaluate inflammatory indices before treatment with autologous antitumor vaccine alone or this vaccine plus metronomic chemotherapy (MC) to predict response and prognosis. The indices included the neutrophil–lymphocyte ratio (NRL), platelet–lymphocyte ratio (PLR), monocyte–lymphocyte ratio (MLR), systemic immune-inflammation index (SII), C-reactive-protein–albumin ratio (CRP/ALB), lactate dehydrogenase level (LDH), frequency of blood lymphocyte subsets (CD4+, CD8+, Treg, and CD4/CD8 ratio) and frequency of blood myeloid-derived suppressor cells (MDSCs: monocytic [M]- MDSCs, and granulocytic [PMN]-MDSCs). Blood samples were collected from 25 dogs with oral melanoma treated with the autologous antitumor vaccine and from nine dogs that received MC plus vaccine before surgery. There were no statistically significant differences in the progression-free survival (PFS) or overall survival (OS) between the groups. In addition to the clinical stage, the CRP/ALB ratio and blood circulating Tregs in the univariate analysis showed an association with PFS and OS, and thus were selected for multivariable analysis. The CRP/ALB ratio was associated with PFS [hazard ratio (HR), 1.1; 95% confidence interval (CI), 1.0–1.1; p = 0.017] and OS [HR, 1; 95%CI, 1.0–1.1; p = 0.023]. Similarly, Treg was associated with PFS (HR, 1.6; 95% CI, 1.2–2.1; p = 0.001) and OS (HR, 1.6; 95% CI, 1.2–2.1; p = 0.001). Furthermore, canine patients with a CRP/ALB ratio above the cut-off point of 1.9 (established by receiver operating characteristic curve analysis) had worse PFS and OS, indicating the impact of the preoperative CRP/ALB ratio on the PFS and OS of dogs with oral melanoma. The CRP/ALB ratio and frequency of circulating Tregs are potential prognostic markers in dogs with oral melanoma.

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Characterization of myeloid-derived suppressor cells and cytokines GM-CSF, IL-10 and MCP-1 in dogs with malignant melanoma receiving a GD3-based immunotherapy

Cited by 18 publications

References 73 publications

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Association of Systemic Inflammatory and Immune Indices With Survival in Canine Patients With Oral Melanoma, Treated With Experimental Immunotherapy Alone or Experimental Immunotherapy Plus Metronomic Chemotherapy

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