;PROJECT 4 : Immune Tolerance and Stem Cell Transplantation Impaired immune responses are common in cancer and a particular feature of chronic lymphocytic leukemia (CLL). The immune dyfuction in CLL is characterised by hypogammaglobulinemia and autoimmune phenomena and infectious complications are a major cause of morbidity and mortality in this disease. Previous work in this Program has demonstrated a direct effect of CLL cells on T cells, both in human samples and in the Eji-TCL1 transgenic mouse model of this disease, that result in changes in actin polymerization in T and NK cells and failure of these cells to mount effective immune synapses with antigen presenting cells. The central hypothesis of this project Is that specific T cell defects result from interaction of CLL cells with the patient's immune system and that repair of these defects will be required to maximize T cell mediated immune responses in vivo. We therefore seek to characterize the basis for defective immune cell function in CLL and repair these defects for future therapeutic intervention. We shall examine this in human samples from patients with CLL and in an E(i-TCL1 transgenic mouse model of this disease. Since most agents that are used to treat CLL also add to the immune suppression, the project will determine whether novel agents in clinical trials in this Program have impact on the host immune system and are therefore likely to worsen immune function. Work will also be performed to assess the nature of T cell mediated anti-tumor immune responses against CLL cells and to determine if these specific T cell responses occur following allogeneic stem cell transplantation for CLL. The goal here is to characterize the nature ofthe graft versus leukemia effect in CLL. To address these issues this project will address the following specific aims: First, to define the molecular mechanism whereby molecules expressed by CLL cells induce dysfunction in T and NK cell in patients with CLL and the role of immunomodulatory drug intervention to repair these defects. The goal here is to improve immune function in CLL patients. Second, to assess the impact of in prevention of induction of T cell defects vivo in the Emu-TCLI transgenic mouse model of CLL and asses its impact on disease progression. Third, to characterize targets of graft versus leukemia effect in CLL after allogeneic stem cell transplantation in CTN/ CALGB 100701. Taken together, these studies will assess the impact of immune mediated responses in CLL.

Public Health Relevance

This project has demonstrated that CLL cells induce defects in the host immune. In keeping with our original hypothesis that CLL would act as a model disease, based on this knowledge, we have demonstrated similar defects in actin polymerization in T cells in patients with other hematologic malignancies including acute myeloid leukemia, follicular lymphoma, diffuse large cell lymphoma, myeloma, breast, ovarian and pancreatic cancer. Findings from this Project therefore have broad implications in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA081534-14
Application #
8733428
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
14
Fiscal Year
2014
Total Cost
$239,893
Indirect Cost
$35,113
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Gribben, John G (2018) How and when I do allogeneic transplant in CLL. Blood 132:31-39
Sivina, Mariela; Werner, Lillian; Rassenti, Laura et al. (2018) Dynamic changes in CCL3 and CCL4 plasma concentrations in patients with chronic lymphocytic leukaemia managed with observation. Br J Haematol 180:597-600
Ott, Christopher J; Federation, Alexander J; Schwartz, Logan S et al. (2018) Enhancer Architecture and Essential Core Regulatory Circuitry of Chronic Lymphocytic Leukemia. Cancer Cell 34:982-995.e7
Balatti, Veronica; Tomasello, Luisa; Rassenti, Laura Z et al. (2018) miR-125a and miR-34a expression predicts Richter syndrome in chronic lymphocytic leukemia patients. Blood 132:2179-2182
Vangapandu, Hima V; Chen, Huiqin; Wierda, William G et al. (2018) Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells. Leuk Lymphoma 59:1427-1438
Yu, Jian; Chen, Yun; Chen, Liguang et al. (2018) Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma. Oncotarget 9:24731-24736
Barr, Paul M; Robak, Tadeusz; Owen, Carolyn et al. (2018) Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica 103:1502-1510
Kondo, K; Shaim, H; Thompson, P A et al. (2018) Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 32:960-970
Hasan, Md Kamrul; Yu, Jian; Widhopf 2nd, George F et al. (2018) Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia. Blood 132:170-178
Ten Hacken, Elisa; Valentin, Rebecca; Regis, Fara Faye D et al. (2018) Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies. JCI Insight 3:

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