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MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer.

Olesch C, Sha W, Angioni C, Sha LK, Açaf E, Patrignani P, Jakobsson PJ, Radeke HH, Grösch S, Geisslinger G, von Knethen A, Weigert A, Brüne B - Oncotarget (2015)

Bottom Line: Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression.Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice.In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.

ABSTRACT
Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1(-/-) PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1(-/-) macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.

No MeSH data available.


Related in: MedlinePlus

mPGES-1-deficiency impairs PyMT tumor growth(A) Prostanoids PGE2, PGD2, PGF2α, TxB2, and 6 keto PGF1α in wildtype (WT; n=8) and mPGES-1−/− (n = 10) PyMT tumors were measured by LC-MS/MS. Data are means ± SEM. (B) The average number of tumor-bearing mammary glands per mouse is displayed. (C,D) PyMT mice were sacrificed 20 weeks after birth. (C) Tumor burden is defined as the ratio of total tumor mass and mouse body weight. (D) Tumors were categorized and their respective numbers are displayed. (B-D) Data are means ± SEM of 20 WT and 18 mPGES-1−/− mice. p-values were calculated using student's t-test (C) or two-way ANOVA with Bonferroni's correction (A,B). Asterisks indicate significant differences between experimental groups (*, p ≤ .05, **, p ≤ .01, ***, p ≤ .001).
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Figure 5: mPGES-1-deficiency impairs PyMT tumor growth(A) Prostanoids PGE2, PGD2, PGF2α, TxB2, and 6 keto PGF1α in wildtype (WT; n=8) and mPGES-1−/− (n = 10) PyMT tumors were measured by LC-MS/MS. Data are means ± SEM. (B) The average number of tumor-bearing mammary glands per mouse is displayed. (C,D) PyMT mice were sacrificed 20 weeks after birth. (C) Tumor burden is defined as the ratio of total tumor mass and mouse body weight. (D) Tumors were categorized and their respective numbers are displayed. (B-D) Data are means ± SEM of 20 WT and 18 mPGES-1−/− mice. p-values were calculated using student's t-test (C) or two-way ANOVA with Bonferroni's correction (A,B). Asterisks indicate significant differences between experimental groups (*, p ≤ .05, **, p ≤ .01, ***, p ≤ .001).

Mentions: We asked whether regulation of parameters affecting tumor killing in the human in vitro setting could be recapitulated in a breast cancer model in vivo. We crossed mPGES-1-deficient mice into the PyMT background, to generate female mice that develop spontaneous breast cancer [20]. Tumors were first observed 8 weeks after birth and tumor development was monitored until sacrifice. MPGES-1-deficiency resulted in strongly reduced PGE2 levels in tumors after sacrifice (20 weeks) (Figure 5A). Importantly, shunting of arachidonic acid towards the production of other prostaglandins was also excluded in PyMT tumors (Figure 5A). Accordingly, both COX-1 and COX-2 mRNA were expressed in PyMT tumors, independent of the mPGES-1 status (Figure S3A). Lack of mPGES-1 delayed tumor development and reduced numbers of tumor-bearing mammary glands per mouse compared to WT PyMT mice (Figure 5B). After 20 weeks, loss of mPGES-1 still resulted in significantly reduced tumor mass (Figure 5C). However, the relative distribution of tumor size in mPGES-1-deficient PyMT mice was not different from WT PyMT mice (Figure 5D). Apparently, the absence of PGE2 enhances tumor dormancy rather than affecting tumor growth kinetics. This observation might indicate a role of mPGES-1-derived PGE2 in modulating tumor immune escape [27].


MPGES-1-derived PGE2 suppresses CD80 expression on tumor-associated phagocytes to inhibit anti-tumor immune responses in breast cancer.

Olesch C, Sha W, Angioni C, Sha LK, Açaf E, Patrignani P, Jakobsson PJ, Radeke HH, Grösch S, Geisslinger G, von Knethen A, Weigert A, Brüne B - Oncotarget (2015)

mPGES-1-deficiency impairs PyMT tumor growth(A) Prostanoids PGE2, PGD2, PGF2α, TxB2, and 6 keto PGF1α in wildtype (WT; n=8) and mPGES-1−/− (n = 10) PyMT tumors were measured by LC-MS/MS. Data are means ± SEM. (B) The average number of tumor-bearing mammary glands per mouse is displayed. (C,D) PyMT mice were sacrificed 20 weeks after birth. (C) Tumor burden is defined as the ratio of total tumor mass and mouse body weight. (D) Tumors were categorized and their respective numbers are displayed. (B-D) Data are means ± SEM of 20 WT and 18 mPGES-1−/− mice. p-values were calculated using student's t-test (C) or two-way ANOVA with Bonferroni's correction (A,B). Asterisks indicate significant differences between experimental groups (*, p ≤ .05, **, p ≤ .01, ***, p ≤ .001).
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Related In: Results  -  Collection

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Figure 5: mPGES-1-deficiency impairs PyMT tumor growth(A) Prostanoids PGE2, PGD2, PGF2α, TxB2, and 6 keto PGF1α in wildtype (WT; n=8) and mPGES-1−/− (n = 10) PyMT tumors were measured by LC-MS/MS. Data are means ± SEM. (B) The average number of tumor-bearing mammary glands per mouse is displayed. (C,D) PyMT mice were sacrificed 20 weeks after birth. (C) Tumor burden is defined as the ratio of total tumor mass and mouse body weight. (D) Tumors were categorized and their respective numbers are displayed. (B-D) Data are means ± SEM of 20 WT and 18 mPGES-1−/− mice. p-values were calculated using student's t-test (C) or two-way ANOVA with Bonferroni's correction (A,B). Asterisks indicate significant differences between experimental groups (*, p ≤ .05, **, p ≤ .01, ***, p ≤ .001).
Mentions: We asked whether regulation of parameters affecting tumor killing in the human in vitro setting could be recapitulated in a breast cancer model in vivo. We crossed mPGES-1-deficient mice into the PyMT background, to generate female mice that develop spontaneous breast cancer [20]. Tumors were first observed 8 weeks after birth and tumor development was monitored until sacrifice. MPGES-1-deficiency resulted in strongly reduced PGE2 levels in tumors after sacrifice (20 weeks) (Figure 5A). Importantly, shunting of arachidonic acid towards the production of other prostaglandins was also excluded in PyMT tumors (Figure 5A). Accordingly, both COX-1 and COX-2 mRNA were expressed in PyMT tumors, independent of the mPGES-1 status (Figure S3A). Lack of mPGES-1 delayed tumor development and reduced numbers of tumor-bearing mammary glands per mouse compared to WT PyMT mice (Figure 5B). After 20 weeks, loss of mPGES-1 still resulted in significantly reduced tumor mass (Figure 5C). However, the relative distribution of tumor size in mPGES-1-deficient PyMT mice was not different from WT PyMT mice (Figure 5D). Apparently, the absence of PGE2 enhances tumor dormancy rather than affecting tumor growth kinetics. This observation might indicate a role of mPGES-1-derived PGE2 in modulating tumor immune escape [27].

Bottom Line: Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression.Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice.In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.

ABSTRACT
Prostaglandin E2 (PGE2) favors multiple aspects of tumor development and immune evasion. Therefore, microsomal prostaglandin E synthase (mPGES-1/-2), is a potential target for cancer therapy. We explored whether inhibiting mPGES-1 in human and mouse models of breast cancer affects tumor-associated immunity. A new model of breast tumor spheroid killing by human PBMCs was developed. In this model, tumor killing required CD80 expression by tumor-associated phagocytes to trigger cytotoxic T cell activation. Pharmacological mPGES-1 inhibition increased CD80 expression, whereas addition of PGE2, a prostaglandin E2 receptor 2 (EP2) agonist, or activation of signaling downstream of EP2 reduced CD80 expression. Genetic ablation of mPGES-1 resulted in markedly reduced tumor growth in PyMT mice. Macrophages of mPGES-1(-/-) PyMT mice indeed expressed elevated levels of CD80 compared to their wildtype counterparts. CD80 expression in tumor-spheroid infiltrating mPGES-1(-/-) macrophages translated into antigen-specific cytotoxic T cell activation. In conclusion, mPGES-1 inhibition elevates CD80 expression by tumor-associated phagocytes to restrict tumor growth. We propose that mPGES-1 inhibition in combination with immune cell activation might be part of a therapeutic strategy to overcome the immunosuppressive tumor microenvironment.

No MeSH data available.


Related in: MedlinePlus