Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models

Elsas, Marit van; Kleinovink, Jan Willem; Moerland, Matthijs; Feiss, Gary; Beyrend, Guillaume; Arens, Ramon; Mei, Hailiang; Nibbering, Peter H.; Jirka, Silvana M.G.; Hall, Thorbald van; Burg, Sjoerd H. van der

doi:10.1136/jitc-2020-000877

Cited by 8 publications

(6 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our characterization of the TME complements previous reports investigating the immune cell composition in various tumor models based on flow cytometry or RNA sequencing ( 58 , 63 – 65 ). Although some variations between the different studies are seen, our data is largely in line with these reports.…”

Section: Discussionsupporting

confidence: 75%

Dissecting tumor microenvironment heterogeneity in syngeneic mouse models: insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells

Carretta,

Thorseth,

Schina

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Murine syngeneic tumor models have been used extensively for cancer research for several decades and have been instrumental in driving the discovery and development of cancer immunotherapies. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cell lines can lead to the formation of unique tumor microenvironments (TMEs). To gain more knowledge from studies based on syngeneic tumor models, it is essential to obtain an in-depth understanding of the cellular and molecular composition of the TME in the different models. Additionally, other parameters that are important for cancer progression, such as collagen content and mechanical tissue stiffness across syngeneic tumor models have not previously been reported. Here, we compare the TME of tumors derived from six common syngeneic tumor models. Using flow cytometry and transcriptomic analyses, we show that strikingly unique TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid, and stromal cells in the tumors. Gene expression analyses support the different cellular composition of the TMEs and indicate that distinct immunosuppressive mechanisms are employed depending on the tumor model. Cancer-associated fibroblasts (CAFs) also acquire very different phenotypes across the tumor models. These differences include differential expression of genes encoding extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and immunosuppressive factors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME, and flow cytometry analyses show increased PD-L1 expression by CAFs in the immunogenic tumor models, MC38 and CT26. Comparison with CAF subsets identified in other studies shows that CAFs are skewed towards specific subsets depending on the model. In athymic mice lacking tumor-infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers. Our data underscores that CAFs can be involved in the formation of an immunosuppressive TME.

show abstract

Section: Discussionsupporting

confidence: 75%

Dissecting tumor microenvironment heterogeneity in syngeneic mouse models: insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells

Carretta,

Thorseth,

Schina

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Ly6G expression on granulocytes can be separated into Ly6G hi and Ly6G int fractions, the former of which represents a more mature cell population ( 48 ). Granulocytes expressing lower levels of Ly6C are expanded in relation to tumor growth ( 49 ). Thus, these studies suggested that increased expression of Ly6G and/or Ly6C may be indicative of granulocyte maturation.…”

Section: Resultsmentioning

confidence: 99%

Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression

Colligan¹,

Amitrano²,

Zollo³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8 + T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.

show abstract

“…Tumor-infiltrating tumor-reactive T cells function as a tissue-specific trigger for tumor destruction but are not always necessary 39 or sufficient 15 for tissue damage. We and others have shown that the T-cell-driven regression of tumors may require the attraction and activation of tumoricidal phagocytic macrophages 14 26 34 or neutrophils 40 to deliver the final cytotoxic insult. While neutrophils display antitumor activity in the TC-1 model, 40 we showed here that they do not contribute to the efficacy of therapeutic vaccination.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have shown that the T-cell-driven regression of tumors may require the attraction and activation of tumoricidal phagocytic macrophages 14 26 34 or neutrophils 40 to deliver the final cytotoxic insult. While neutrophils display antitumor activity in the TC-1 model, 40 we showed here that they do not contribute to the efficacy of therapeutic vaccination. The requirement of T cells to deliver the trigger and macrophages to fully execute the cytotoxic program in cancer cells fits well with the concept of programmed cell removal, linking programmed cell death to the removal of the dying cell.…”

Section: Discussionmentioning

confidence: 99%

IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

Nejad

Labrie

Elsas

et al. 2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundHigh serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.MethodsIL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6rafl/fl×LysMcre+ mice.ResultsOur therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl×LysMcre+ but not cre-negative control mice, while no differences in the vaccine-induced CD8+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.ConclusionIL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.

show abstract

Host genetics and tumor environment determine the functional impact of neutrophils in mouse tumor models

Cited by 8 publications

References 52 publications

Dissecting tumor microenvironment heterogeneity in syngeneic mouse models: insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells

Dissecting tumor microenvironment heterogeneity in syngeneic mouse models: insights on cancer-associated fibroblast phenotypes shaped by infiltrating T cells

Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression

IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

Contact Info

Product

Resources

About