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Modulators of arginine metabolism support cancer immunosurveillance.

Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M - BMC Immunol. (2009)

Bottom Line: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity.Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy. giusy_capuano@hotmail.com

ABSTRACT

Background: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.

Results: We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.

Conclusion: Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

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Related in: MedlinePlus

MDSC suppress T cells proliferation. MDSC were purified as CD11b+ cells from the spleen of C26GM (A, B) and RMA (C) tumor bearing mice by immunomagnetic beads sorting as detailed in the Materials and Methods section. CD11b+ cells were added at a final concentration of 20% to a mixed leukocyte culture set up with splenocytes, as responders, stimulated with anti-CD3 and anti-CD28 antibodies (A, C) or with an equal number of γ-irradiated C57BL/6 splenocytes (B). Data are representative of at least two experiments and are expressed as the cpm mean ± SD of triplicates. Student's T test: **0.001 < p < 0.05.
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Figure 2: MDSC suppress T cells proliferation. MDSC were purified as CD11b+ cells from the spleen of C26GM (A, B) and RMA (C) tumor bearing mice by immunomagnetic beads sorting as detailed in the Materials and Methods section. CD11b+ cells were added at a final concentration of 20% to a mixed leukocyte culture set up with splenocytes, as responders, stimulated with anti-CD3 and anti-CD28 antibodies (A, C) or with an equal number of γ-irradiated C57BL/6 splenocytes (B). Data are representative of at least two experiments and are expressed as the cpm mean ± SD of triplicates. Student's T test: **0.001 < p < 0.05.

Mentions: To verify whether the CD11b+ cells accumulating in tumor-bearing BALB/c mice were "bona fide" MDSC, splenic CD11b+ cells were purified by magnetic bead sorting, and tested for their immunosuppressive activity in standard in vitro proliferation assays. Indeed, CD11b+ cells purified from C26GM tumor-bearing mice were able to substantially abrogate the proliferation of BALB/c splenocytes stimulated with either anti-CD3 and anti-CD28 antibodies (Fig. 2A) or γ-irradiated C57BL/6 splenocytes (Fig. 2B).


Modulators of arginine metabolism support cancer immunosurveillance.

Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M - BMC Immunol. (2009)

MDSC suppress T cells proliferation. MDSC were purified as CD11b+ cells from the spleen of C26GM (A, B) and RMA (C) tumor bearing mice by immunomagnetic beads sorting as detailed in the Materials and Methods section. CD11b+ cells were added at a final concentration of 20% to a mixed leukocyte culture set up with splenocytes, as responders, stimulated with anti-CD3 and anti-CD28 antibodies (A, C) or with an equal number of γ-irradiated C57BL/6 splenocytes (B). Data are representative of at least two experiments and are expressed as the cpm mean ± SD of triplicates. Student's T test: **0.001 < p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2648942&req=5

Figure 2: MDSC suppress T cells proliferation. MDSC were purified as CD11b+ cells from the spleen of C26GM (A, B) and RMA (C) tumor bearing mice by immunomagnetic beads sorting as detailed in the Materials and Methods section. CD11b+ cells were added at a final concentration of 20% to a mixed leukocyte culture set up with splenocytes, as responders, stimulated with anti-CD3 and anti-CD28 antibodies (A, C) or with an equal number of γ-irradiated C57BL/6 splenocytes (B). Data are representative of at least two experiments and are expressed as the cpm mean ± SD of triplicates. Student's T test: **0.001 < p < 0.05.
Mentions: To verify whether the CD11b+ cells accumulating in tumor-bearing BALB/c mice were "bona fide" MDSC, splenic CD11b+ cells were purified by magnetic bead sorting, and tested for their immunosuppressive activity in standard in vitro proliferation assays. Indeed, CD11b+ cells purified from C26GM tumor-bearing mice were able to substantially abrogate the proliferation of BALB/c splenocytes stimulated with either anti-CD3 and anti-CD28 antibodies (Fig. 2A) or γ-irradiated C57BL/6 splenocytes (Fig. 2B).

Bottom Line: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity.Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy. giusy_capuano@hotmail.com

ABSTRACT

Background: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.

Results: We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.

Conclusion: Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

Show MeSH
Related in: MedlinePlus