Song complexity and stereotypy in the song sparrow {Melospiza melodia) as indicators of constitutive immune function

Indicator models of sexual selection predict that ornaments may reliably advertise male quality and in particular, viability. Songbird song is a well-studied ornament used by females to evaluate potential mates. In this thesis I examine the reliability of two different aspects of song, thought to develop over different timescales, in indicating immune function of breeding male song sparrows [Melospiza melodia). Immunity was assessed through multiple measures of constitutive innate immune function. Overall, I observed a pattern of constitutive immunity that suggests within- system trade-offs. Moreover, this pattern was associated with measures of song complexity. Male song sparrows with more complex song had significantly higher levels of circulating protective proteins (natural antibody, haptoglobin and lysozyme), but showed decreased levels and/or activity of peripheral blood cellular immunity. I observed no significant association between measures of song stereotypy and constitutive immune function. Ultimately, this study suggests that song complexity (although not song stereotypy) may be associated with individual variation in self-maintenance strategies, rather than a simple indicator of quality as originally hypothesize

Mononuclear Phagocyte Modulation of the Tumor Microenvironment and Control of Anti-tumor Immunity

Tumors are heterogeneously comprised of various cell types that make up a complex tissue-like structure, where cancer cells interact with various non-malignant cells. Immune cells represent one of these non-malignant cell types, and are particularly suitable as targets for anti-cancer therapeutics. Therapeutics that target the immune system (Immunotherapeutics), which are currently in clinical application, aim to restore immune responses to cancer cells by inhibiting the immune checkpoints that dampen lymphocyte responses. The efficacy of these immunotherapeutics results in good prognosis for some patients. Unfortunately, there are many non-responders, and we are only now just starting to discern the mechanisms that govern response efficacy. Targeting these immune checkpoints, with αPD-1 and αCTLA-4 monoclonal antibodies, restores anti-tumor effector function to dysfunctional tumor infiltrating lymphocytes, and facilitates the reduction of regulatory T cells. However, there are other aspects of tumor immunology that are unaffected by these drugs. Combinatorial treatment strategies that amplify the effects of current immune modulating drugs are thus predicted to enhance response efficacy. It is well established that myeloid cells contribute to oncogenesis, but how the constellation of receptors they express regulates their functions within the tumor microenvironment is less clear. Furthermore, cells of the mononuclear phagocytic system have the potential to function in a pro-tumoral capacity, or to promote anti-tumor immunity for cancer cell elimination. Here we demonstrate that autocrine and paracrine EGFR signaling between intratumoral macrophages and cancer cells facilitates tumorigenesis through macrophage mediated trophic support. Specifically, we show a novel AhR-AREG axis facilitates maintenance of the tumor microenvironment in BRCA1-associated breast cancer. Alternatively, in a syngeneic melanoma model we illustrate that Toso (FCMR), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer to inhibit anti-tumor immunity. Furthermore, Toso negatively regulated the activation and migratory capacity of skin-associated myeloid cells in vivo, and bone-marrow derived dendritic cell-dependent T cell activation in vitro. Importantly, preliminary data indicates therapeutically targeting Ahr in BRCA1-associated cancers, or Toso in melanoma, may improve patient prognosis. Overall, these results suggest that targeting myeloid cell function within the TME represents a potential therapeutic avenue for bolstering current checkpoint immunotherapeutics.Ph.D