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The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.

Hermann-Kleiter N, Klepsch V, Wallner S, Siegmund K, Klepsch S, Tuzlak S, Villunger A, Kaminski S, Pfeifhofer-Obermair C, Gruber T, Wolf D, Baier G - Cell Rep (2015)

Bottom Line: Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily.Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds.Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.

View Article: PubMed Central - PubMed

Affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: natascha.kleiter@i-med.ac.at.

No MeSH data available.


Related in: MedlinePlus

Reduced Metastasis and Anti-Tumor Memory Depends on NR2F6 in T Cells(A) Gross examination of representative metastatic tumor lungs at day 14 and day 19 after tumor inoculation of either Nr2f6+/+ mice (n = 10) or Nr2f6−/− mice (n = 9) i.v.-injected B16-F10.(B) Bar chart depict numbers of lung tumor foci on day 14 (p = 0.002) and day 19 (p = 0.02) after tumor induction in Nr2f6+/+ mice and Nr2f6−/− mice.(C) Long-lasting anti-tumor memory is demonstrated after injection of EG7 tumor cells: Nr2f6−/− mice (n = 6), which had received 1.5 × 105 EG7 cells subcutaneously at 8–12 weeks of age and rejected the primary tumor, were subsequently re-challenged after 10 months with a 10-fold higher dose of EG7 cells. In contrast to age- and sex-matched naive Nr2f6+/+ mice (n = 6) and naive Nr2f6−/− mice (n = 6) controls, 80% of memory Nr2f6−/− mice were able to reject the 10-fold higher tumor dose.(D) Kaplan-Meier survival curves of age-matched naive Nr2f6+/+, naive Nr2f6−/−, and memory Nr2f6−/− mice that received 1.5 × 106 EG7 cells subcutaneously (p < 0.001), statistically analyzed by log-rank test.(E) Enhanced tumor rejection is dependent on Nr2f6−/− T lymphocytes. The kinetics of tumor cell growth in Rag1−/− mice reconstituted with PBS, 1 × 107 CD3+ Nr2f6+/+, or 1 × 107 CD3+ Nr2f6−/− T cells. The average size of Rag1−/− PBS tumors at 17 days was 2,034 mm3 (±156 SEM; n = 5), compared with 1,131 mm3 (±269 SEM; n = 8) in Rag1−/−CD3Nr2f6+/+ and 138 mm3 (±54 SEM; n = 8; p < 0.01) in Rag1−/−CD3Nr2f6−/− mice. One-half of the mice were killed at day 17 after tumor induction in order to analyze tumor dLNs.(F) Flow cytometry analyses revealed increased CD4+ T cell numbers in the dLNs of tumor-bearing Rag1−/−CD3Nr2f6−/− mice (p = 0.03) when compared to tumor dLNs of Rag1−/−CD3Nr2f6+/+. The data are depicted as bar chart representing CD4+ cells as percentage of total cells. Summary graphs show the mean ± SEM and were statistically analyzed by Student’s t test.(G and H) Adoptive transfer of Nr2f6−/−but not Nr2f6+/+ CD3+ or OT-I cells into B16-OVA tumor-bearing wild-type mice significantly reduces tumor growth. (G) Kinetics of B16-OVA tumor growth after a single therapeutic adoptive transfer of 3 × 106 OT-I donor T cells derived from either Nr2f6−/− or Nr2f6+/+ mice (p = 0.0083) or (H) after single transfer of 1 × 107 CD3+ T cells again derived from either Nr2f6−/− or Nr2f6+/+ mice into wild-type mice on day 7 after tumor induction (p = 0.001). Data are representative of at least two independent experiments (naive recipients n ≥ 7/group, OT-I recipients n = 6/group); graphs show the mean ± SEM statistically analyzed by two-way ANOVA.
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fig5: Reduced Metastasis and Anti-Tumor Memory Depends on NR2F6 in T Cells(A) Gross examination of representative metastatic tumor lungs at day 14 and day 19 after tumor inoculation of either Nr2f6+/+ mice (n = 10) or Nr2f6−/− mice (n = 9) i.v.-injected B16-F10.(B) Bar chart depict numbers of lung tumor foci on day 14 (p = 0.002) and day 19 (p = 0.02) after tumor induction in Nr2f6+/+ mice and Nr2f6−/− mice.(C) Long-lasting anti-tumor memory is demonstrated after injection of EG7 tumor cells: Nr2f6−/− mice (n = 6), which had received 1.5 × 105 EG7 cells subcutaneously at 8–12 weeks of age and rejected the primary tumor, were subsequently re-challenged after 10 months with a 10-fold higher dose of EG7 cells. In contrast to age- and sex-matched naive Nr2f6+/+ mice (n = 6) and naive Nr2f6−/− mice (n = 6) controls, 80% of memory Nr2f6−/− mice were able to reject the 10-fold higher tumor dose.(D) Kaplan-Meier survival curves of age-matched naive Nr2f6+/+, naive Nr2f6−/−, and memory Nr2f6−/− mice that received 1.5 × 106 EG7 cells subcutaneously (p < 0.001), statistically analyzed by log-rank test.(E) Enhanced tumor rejection is dependent on Nr2f6−/− T lymphocytes. The kinetics of tumor cell growth in Rag1−/− mice reconstituted with PBS, 1 × 107 CD3+ Nr2f6+/+, or 1 × 107 CD3+ Nr2f6−/− T cells. The average size of Rag1−/− PBS tumors at 17 days was 2,034 mm3 (±156 SEM; n = 5), compared with 1,131 mm3 (±269 SEM; n = 8) in Rag1−/−CD3Nr2f6+/+ and 138 mm3 (±54 SEM; n = 8; p < 0.01) in Rag1−/−CD3Nr2f6−/− mice. One-half of the mice were killed at day 17 after tumor induction in order to analyze tumor dLNs.(F) Flow cytometry analyses revealed increased CD4+ T cell numbers in the dLNs of tumor-bearing Rag1−/−CD3Nr2f6−/− mice (p = 0.03) when compared to tumor dLNs of Rag1−/−CD3Nr2f6+/+. The data are depicted as bar chart representing CD4+ cells as percentage of total cells. Summary graphs show the mean ± SEM and were statistically analyzed by Student’s t test.(G and H) Adoptive transfer of Nr2f6−/−but not Nr2f6+/+ CD3+ or OT-I cells into B16-OVA tumor-bearing wild-type mice significantly reduces tumor growth. (G) Kinetics of B16-OVA tumor growth after a single therapeutic adoptive transfer of 3 × 106 OT-I donor T cells derived from either Nr2f6−/− or Nr2f6+/+ mice (p = 0.0083) or (H) after single transfer of 1 × 107 CD3+ T cells again derived from either Nr2f6−/− or Nr2f6+/+ mice into wild-type mice on day 7 after tumor induction (p = 0.001). Data are representative of at least two independent experiments (naive recipients n ≥ 7/group, OT-I recipients n = 6/group); graphs show the mean ± SEM statistically analyzed by two-way ANOVA.

Mentions: The impact of Nr2f6 deficiency on tumor metastasis was next evaluated by challenging each mouse genotype with intravenously (i.v.) administered B16-F10 cells, which are known to form lung metastases upon i.v. injection. Similar to our previous data, formation of lung metastases was significantly reduced at day 14 and 19 post-injection, as quantified by reduction of the number of tumor foci in the lungs of Nr2f6-deficient mice (Figures 5A and 5B). Thus, deficiency of Nr2f6 in non-cancer cells appears to strongly enhance the anti-metastatic activity of the immune system.


The Nuclear Orphan Receptor NR2F6 Is a Central Checkpoint for Cancer Immune Surveillance.

Hermann-Kleiter N, Klepsch V, Wallner S, Siegmund K, Klepsch S, Tuzlak S, Villunger A, Kaminski S, Pfeifhofer-Obermair C, Gruber T, Wolf D, Baier G - Cell Rep (2015)

Reduced Metastasis and Anti-Tumor Memory Depends on NR2F6 in T Cells(A) Gross examination of representative metastatic tumor lungs at day 14 and day 19 after tumor inoculation of either Nr2f6+/+ mice (n = 10) or Nr2f6−/− mice (n = 9) i.v.-injected B16-F10.(B) Bar chart depict numbers of lung tumor foci on day 14 (p = 0.002) and day 19 (p = 0.02) after tumor induction in Nr2f6+/+ mice and Nr2f6−/− mice.(C) Long-lasting anti-tumor memory is demonstrated after injection of EG7 tumor cells: Nr2f6−/− mice (n = 6), which had received 1.5 × 105 EG7 cells subcutaneously at 8–12 weeks of age and rejected the primary tumor, were subsequently re-challenged after 10 months with a 10-fold higher dose of EG7 cells. In contrast to age- and sex-matched naive Nr2f6+/+ mice (n = 6) and naive Nr2f6−/− mice (n = 6) controls, 80% of memory Nr2f6−/− mice were able to reject the 10-fold higher tumor dose.(D) Kaplan-Meier survival curves of age-matched naive Nr2f6+/+, naive Nr2f6−/−, and memory Nr2f6−/− mice that received 1.5 × 106 EG7 cells subcutaneously (p < 0.001), statistically analyzed by log-rank test.(E) Enhanced tumor rejection is dependent on Nr2f6−/− T lymphocytes. The kinetics of tumor cell growth in Rag1−/− mice reconstituted with PBS, 1 × 107 CD3+ Nr2f6+/+, or 1 × 107 CD3+ Nr2f6−/− T cells. The average size of Rag1−/− PBS tumors at 17 days was 2,034 mm3 (±156 SEM; n = 5), compared with 1,131 mm3 (±269 SEM; n = 8) in Rag1−/−CD3Nr2f6+/+ and 138 mm3 (±54 SEM; n = 8; p < 0.01) in Rag1−/−CD3Nr2f6−/− mice. One-half of the mice were killed at day 17 after tumor induction in order to analyze tumor dLNs.(F) Flow cytometry analyses revealed increased CD4+ T cell numbers in the dLNs of tumor-bearing Rag1−/−CD3Nr2f6−/− mice (p = 0.03) when compared to tumor dLNs of Rag1−/−CD3Nr2f6+/+. The data are depicted as bar chart representing CD4+ cells as percentage of total cells. Summary graphs show the mean ± SEM and were statistically analyzed by Student’s t test.(G and H) Adoptive transfer of Nr2f6−/−but not Nr2f6+/+ CD3+ or OT-I cells into B16-OVA tumor-bearing wild-type mice significantly reduces tumor growth. (G) Kinetics of B16-OVA tumor growth after a single therapeutic adoptive transfer of 3 × 106 OT-I donor T cells derived from either Nr2f6−/− or Nr2f6+/+ mice (p = 0.0083) or (H) after single transfer of 1 × 107 CD3+ T cells again derived from either Nr2f6−/− or Nr2f6+/+ mice into wild-type mice on day 7 after tumor induction (p = 0.001). Data are representative of at least two independent experiments (naive recipients n ≥ 7/group, OT-I recipients n = 6/group); graphs show the mean ± SEM statistically analyzed by two-way ANOVA.
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fig5: Reduced Metastasis and Anti-Tumor Memory Depends on NR2F6 in T Cells(A) Gross examination of representative metastatic tumor lungs at day 14 and day 19 after tumor inoculation of either Nr2f6+/+ mice (n = 10) or Nr2f6−/− mice (n = 9) i.v.-injected B16-F10.(B) Bar chart depict numbers of lung tumor foci on day 14 (p = 0.002) and day 19 (p = 0.02) after tumor induction in Nr2f6+/+ mice and Nr2f6−/− mice.(C) Long-lasting anti-tumor memory is demonstrated after injection of EG7 tumor cells: Nr2f6−/− mice (n = 6), which had received 1.5 × 105 EG7 cells subcutaneously at 8–12 weeks of age and rejected the primary tumor, were subsequently re-challenged after 10 months with a 10-fold higher dose of EG7 cells. In contrast to age- and sex-matched naive Nr2f6+/+ mice (n = 6) and naive Nr2f6−/− mice (n = 6) controls, 80% of memory Nr2f6−/− mice were able to reject the 10-fold higher tumor dose.(D) Kaplan-Meier survival curves of age-matched naive Nr2f6+/+, naive Nr2f6−/−, and memory Nr2f6−/− mice that received 1.5 × 106 EG7 cells subcutaneously (p < 0.001), statistically analyzed by log-rank test.(E) Enhanced tumor rejection is dependent on Nr2f6−/− T lymphocytes. The kinetics of tumor cell growth in Rag1−/− mice reconstituted with PBS, 1 × 107 CD3+ Nr2f6+/+, or 1 × 107 CD3+ Nr2f6−/− T cells. The average size of Rag1−/− PBS tumors at 17 days was 2,034 mm3 (±156 SEM; n = 5), compared with 1,131 mm3 (±269 SEM; n = 8) in Rag1−/−CD3Nr2f6+/+ and 138 mm3 (±54 SEM; n = 8; p < 0.01) in Rag1−/−CD3Nr2f6−/− mice. One-half of the mice were killed at day 17 after tumor induction in order to analyze tumor dLNs.(F) Flow cytometry analyses revealed increased CD4+ T cell numbers in the dLNs of tumor-bearing Rag1−/−CD3Nr2f6−/− mice (p = 0.03) when compared to tumor dLNs of Rag1−/−CD3Nr2f6+/+. The data are depicted as bar chart representing CD4+ cells as percentage of total cells. Summary graphs show the mean ± SEM and were statistically analyzed by Student’s t test.(G and H) Adoptive transfer of Nr2f6−/−but not Nr2f6+/+ CD3+ or OT-I cells into B16-OVA tumor-bearing wild-type mice significantly reduces tumor growth. (G) Kinetics of B16-OVA tumor growth after a single therapeutic adoptive transfer of 3 × 106 OT-I donor T cells derived from either Nr2f6−/− or Nr2f6+/+ mice (p = 0.0083) or (H) after single transfer of 1 × 107 CD3+ T cells again derived from either Nr2f6−/− or Nr2f6+/+ mice into wild-type mice on day 7 after tumor induction (p = 0.001). Data are representative of at least two independent experiments (naive recipients n ≥ 7/group, OT-I recipients n = 6/group); graphs show the mean ± SEM statistically analyzed by two-way ANOVA.
Mentions: The impact of Nr2f6 deficiency on tumor metastasis was next evaluated by challenging each mouse genotype with intravenously (i.v.) administered B16-F10 cells, which are known to form lung metastases upon i.v. injection. Similar to our previous data, formation of lung metastases was significantly reduced at day 14 and 19 post-injection, as quantified by reduction of the number of tumor foci in the lungs of Nr2f6-deficient mice (Figures 5A and 5B). Thus, deficiency of Nr2f6 in non-cancer cells appears to strongly enhance the anti-metastatic activity of the immune system.

Bottom Line: Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily.Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon γ cytokine promoters, attenuating their transcriptional thresholds.Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.

View Article: PubMed Central - PubMed

Affiliation: Translational Cell Genetics, Department for Pharmacology and Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: natascha.kleiter@i-med.ac.at.

No MeSH data available.


Related in: MedlinePlus