CTL induction of tumoricidal nitric oxide production by intratumoral macrophages is critical for tumor elimination.
Vicetti Miguel RD1, Cherpes TL, Watson LJ, McKenna KC.
1Graduate Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Abstract
To
characterize mechanisms of CTL inhibition within an ocular tumor
microenvironment, tumor-specific CTLs were transferred into mice with
tumors developing within the anterior chamber of the eye or skin. Ocular
tumors were resistant to CTL transfer therapy whereas skin tumors were
sensitive. CTLs infiltrated ocular tumors at higher CTL/tumor ratios
than in skin tumors and demonstrated comparable ex vivo effector
function to CTLs within skin tumors indicating that ocular tumor
progression was not due to decreased CTL accumulation or inhibited CTL
function within the eye. CD11b(+)Gr-1(+)F4/80(-) cells predominated
within ocular tumors, whereas skin tumors were primarily infiltrated by
CD11b(+)Gr-1(-)F4/80(+) macrophages (Ms), suggesting that myeloid
derived suppressor cells may contribute to ocular tumor growth. However,
CD11b(+) myeloid cells isolated from either tumor site suppressed CTL
activity in vitro via NO production. Paradoxically, the regression of
skin tumors by CTL transfer therapy required NO production by
intratumoral Ms indicating that NO-producing intratumoral myeloid cells
did not suppress the effector phase of CTL. Upon CTL transfer,
tumoricidal concentrations of NO were only produced by skin
tumor-associated Ms though ocular tumor-associated Ms demonstrated
comparable expression of inducible NO synthase protein suggesting that
NO synthase enzymatic activity was compromised within the eye.
Correspondingly, in vitro-activated Ms limited tumor growth when
co-injected with tumor cells in the skin but not in the eye. In
conclusion, the decreased capacity of Ms to produce NO within the ocular
microenvironment limits CTL tumoricidal activity allowing ocular tumors
to progress.
J Immunol. 2010 Dec 1;185(11):6706-18. doi: 10.4049/jimmunol.0903411. Epub 2010 Nov 1.
http://www.jimmunol.org/content/185/11/6706.long
Md. Rodolfo Vicetti. Ex-miembro del GII.