The long-term objectives of this project are to define mechanisms of tumor- induced immune suppression of macrophage function. The innate immune system has significant potential to control cancer progression, however the specific molecular cues and pathways by which myeloid cells recognize and target cancer cells are largely undefined. Using murine models combined with phase I investigation;we have demonstrated that IFN-?-associated M1 features of tumor-associated macrophages within the lymphoma microenvironment are associated with tumor responses and prolonged survival. We now propose a multidisciplinary approach that tests our hypotheses regarding mechanisms by which the systemic as well as innate immune response within the brain may control CNS lymphoma progression. Our general strategy is to evaluate lymphoma-associated macrophages in mouse models using in vivo imaging and gene knock-out strategies to define the origin of myeloid cells in the brain that mediate tumor phagocytosis as well as to identify the key signaling pathways involved in lymphoma recognition.
The specific aims are to identify the key receptors and signaling pathways used by macrophages to control lymphoma progression. We envision four goals. (1) Determine the role of the systemic myeloid response in CNS lymphoma, (2) Determine the key receptors and signaling pathways used by macrophages to recognize and elicit phagocytosis of CNS lymphoma, (3) Evaluate the impact of conditional deletions of myeloid genes on lenalidomide and rituximab-dependent responses on CNS lymphoma growth, (4) Identify factors within the CNS microenvironment that attenuate the systemic innate and adaptive immune response to CNS lymphoma. Results of these studies will have implications for a variety of disorders and cancers in which immune surveillance as well as antibody-dependent cell-mediated cytotoxicity are important means of disease control. These studies may lead to the development of new therapies that modulate macrophage programming and potentiate their anti-tumor potency as well as the adaptive immune response.
The long-term objectives of this project are to define mechanisms of tumor-induced suppression of macrophage function in patients. Macrophages are a critical component of antitumor immunity but may be subverted from the classically-activated, or M1 phenotype, which mediates tumor elimination, to an alternatively-activated, M2 phenotype, which promotes tumor progression. Interferon gamma signaling through its receptor is a pivotal regulator of macrophage polarization to the M1 phenotype. Tumors use a variety of mechanisms to disrupt this M1 pathway and subvert anti-tumor immunity. We are performing an innovative, multidisciplinary set of studies to not only evaluate mechanisms by which M1 macrophages recognize and eliminate cancer cells but also the key strategies employed by cancers to disrupt this ability. Results of these studies will promote the development of more effective therapies not only for non-Hodgkin's lymphoma, but also for brain tumors and other malignancies in which immune surveillance is important for disease control.
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|Kasenda, Benjamin; Loeffler, Jay; Illerhaus, Gerald et al. (2016) The role of whole brain radiation in primary CNS lymphoma. Blood 128:32-6|
|Korfel, Agnieszka; Chamberlain, Marc; Neuwelt, Ed et al. (2016) Therapy for Secondary CNS Involvement in Malignant Lymphomas: No Standard Yet! J Clin Oncol 34:1829-30|
|Carnevale, Julia; Rubenstein, James L (2016) The Challenge of Primary Central Nervous System Lymphoma. Hematol Oncol Clin North Am 30:1293-1316|
|Shalabi, Haneen; Angiolillo, Anne; Vezina, Gilbert et al. (2015) Prolonged Complete Response in a Pediatric Patient With Primary Peripheral T-Cell Lymphoma of the Central Nervous System. Pediatr Hematol Oncol 32:529-34|
|Fraser, Eleanor; Gruenberg, Katherine; Rubenstein, James L (2015) New approaches in primary central nervous system lymphoma. Chin Clin Oncol 4:11|
|Okimoto, Ross A; Perry, Arie; Rubenstein, James L (2015) 77-year-old woman with a dural-based mass. Marginal zone B-cell lymphoma (MZBCL). Brain Pathol 25:111-2|
|Wang, Chia-Ching; Carnevale, Julia; Rubenstein, James L (2014) Progress in central nervous system lymphomas. Br J Haematol 166:311-25|
|Kadoch, Cigall; Li, Jing; Wong, Valerie S et al. (2014) Complement activation and intraventricular rituximab distribution in recurrent central nervous system lymphoma. Clin Cancer Res 20:1029-41|
|Ponzoni, M; Issa, S; Batchelor, T T et al. (2014) Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma. Ann Oncol 25:316-22|
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