The long term objectives of this project are to define mechanisms of tumor-induced immune suppression of macrophage function. Macrophages are a critical component of anti- tumor 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. Interleukin-4 (IL-4) signaling through its receptor, IL-4R-a, is a pivotal regulator of macrophage polarization to the M2 phenotype. Disruption of IL-4 signaling may therefore represent a useful strategy to attenuate the subversion of tumor immunity mediated by M2 tumor- associated macrophages. Our general strategy is to define the phenotypic characteristics of tumor macrophages from patients with non-Hodgkin's lymphoma who participate in a phase I immunotherapy trial involving the administration of anti-CD20 antibody into the cerebrospinal fluid in patients with recurrent disease in the brain. In addition, we will use genetic and pharmacologic strategies in mouse models to dissect the effect of cytokine signaling on tumor angiogenesis, macrophage phenotype and immunotherapeutic response in a model of CNS lymphoma.
The specific aims are to define the relationship between IL-4 signaling, macrophage differentiation, lymphoma growth and response to anti-CD20 antibody. We envision five goals: (1) Define subpopulations of tumor macrophages within the CSF and their relationship to IL-4-induced programming, (2) Define the relationship between macrophage polarization to the M2 phenotype and resistance to anti-CD20 antibody, (3) Define the relevant cytokines and chemokines which predict this resistance, (4) Evaluate the relationship between IL-4 expression by tumor vessels, M2 macrophage programming and tumor growth, (5) Determine the impact of defects in cytokine signaling on macrophage polarization and response to anti-CD20 antibody. 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 which modulate macrophage programming and potentiate their anti-tumor potency.
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 anti- tumor 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. Interleukin-4 (IL-4) signaling through its receptor, IL-4R-a, is a pivotal regulator of macrophage polarization to the M2 phenotype. Disruption of IL-4 signaling may therefore represent a useful strategy to attenuate the subversion of tumor immunity mediated by M2 tumor- associated macrophages. Our general strategy is to perform an innovative, multidisciplinary set of studies to test the hypothesis that IL-4 promotes lymphoma growth both by supporting the tumor blood supply and by the subversion of macrophage function. Results of these studies will promote the development of more effective therapies not only for non-Hodgkin's lymphoma, but also for other malignancies in which immune surveillance as well antibody-dependent cell-mediated cytotoxicity are important means of disease control.
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| Rubenstein, James L (2017) Biology of CNS lymphoma and the potential of novel agents. Hematology Am Soc Hematol Educ Program 2017:556-564 |
| Gupta, Neel K; Wang, Chia-Ching; Mannis, Gabriel N et al. (2017) Regression of methotrexate-resistant AIDS-related primary central nervous system lymphoma with lenalidomide plus combination anti-retroviral therapy. Leuk Lymphoma 58:2748-2751 |
| Gupta, Neel K; Nolan, Amber; Omuro, Antonio et al. (2017) Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol 19:99-108 |
| Kasenda, Benjamin; Loeffler, Jay; Illerhaus, Gerald et al. (2016) The role of whole brain radiation in primary CNS lymphoma. Blood 128:32-6 |
| Carnevale, Julia; Rubenstein, James L (2016) The Challenge of Primary Central Nervous System Lymphoma. Hematol Oncol Clin North Am 30:1293-1316 |
| 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 |
| 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 |
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