Melanomas develop within the eye despite the induction of melanoma-specific CD8+ cytolytic T lymphocyte (CTL) responses which indicates that these tumors somehow evade tumoricidal CTL. Uveal melanomas that are infiltrated by myeloid cells are associated with a poor patient prognosis and we were first to demonstrate in an animal model that the failure to control tumor growth in the anterior chamber of the eye correlates with the accumulation of CD11b+ myeloid cells which inhibit CTL responses in vitro via nitric oxide (NO) production. Accordingly, we hypothesize that myeloid cells promote ocular tumor growth by inhibiting CTL responses within the tumor microenvironment. We demonstrate in preliminary studies the novel observation that GR-1+ F4/80 negative CD11b+ cells accumulate within ocular tumors which are resistant to CTL responses, whereas the same tumors developing within the skin which are sensitive to CTL are infiltrated by GR-1 negative/ F4/80+ CD11b+ cells. Hence, immune suppressive mechanisms which maintain "immune privilege" within the eye by attenuating innate and adaptive immune responses may condition ocular tumor associated CD11b+ cells toward an immunosuppressive and not tumoricidal type as well as directly inhibit CTL responses.
Our Specific Aims will test three related alternative hypotheses about the mechanisms that inhibit CTL responses within the ocular tumor microenvironment.
In Aim #1 we will directly determine the influence of tumor associated CD11b+ cell subsets on the tumoricidal activity of CTL effectors by selectively eliminating GR-1+ cells , F4/80+ cells or both cell populations in mice with established eye or skin tumors prior to adoptive transfer of tumor-specific CTL.
In Aim #2 we will determine the influence of NO production on the tumoricidal activity of CTL by transferring tumor-specific CTL into tumor bearing mice that are deficient in NO production. We will also directly evaluate NO mediated immunosuppressive and tumoricidal activity of CD11b+ cell subsets isolated from skin and eye tumors to determine whether inhibited tumoricidal activity by CD11b+ cells within the eye contributes to ocular tumor progression.
In Aim #3 we will determine the influence of ocular expression of immune suppressive molecules (FasL, PD-1L, Trail, and TGF-?) on the tumoricidal activity of CTL by transferring tumor-specific CTL into mice deficient in these molecules before tumor challenge.
Uveal melanomas infiltrated by myeloid cells are associated with a poor patient prognosis. This application will determine the influence of myeloid cells on suppression of tumoricidal immune responses in an ocular tumor microenvironment. Understanding the contribution of myeloid cells to immune suppression and tumor growth may lead to the development of immunotherapies that promote tumor elimination in the eye and prevent metastasis.
|Miller, Maxine R; Mandell, Jonathan B; Beatty, Kelly M et al. (2014) Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFN?- and Fas/FasL-dependent activation of intratumoral macrophages. Cancer Immunol Res 2:1175-85|
|McKenna, Kyle C; Beatty, Kelly M; Scherder, Rebecca C et al. (2013) Ascorbate in aqueous humor augments nitric oxide production by macrophages. J Immunol 190:556-64|
|McKenna, Kyle C; Vicetti Miguel, Rodolfo D; Beatty, Kelly M et al. (2011) A caveat for T cell transfer studies: generation of cytotoxic anti-Thy1.2 antibodies in Thy1.1 congenic mice given Thy1.2+ tumors or T cells. J Leukoc Biol 89:291-300|
|Vicetti Miguel, Rodolfo D; Cherpes, Thomas L; Watson, Leah J et al. (2010) CTL induction of tumoricidal nitric oxide production by intratumoral macrophages is critical for tumor elimination. J Immunol 185:6706-18|