Please enable JavaScript or talk to your local administrator to get JavaScript enabled.

Project

Mechanisms underlying dampening of the immune response in non-muscle invasive bladder cancer (NMIBC)

Funder: Swiss National Science Foundation

Funding period
CHF 302 K
USD 320 K
Funding amount
Abstract
Control of tumor growth by immunotherapy is hindered by a number of obstacles including the ability of tumors to foster a tolerant microenvironment and the activation of various immunosuppressive mechanisms that may act in concert to counteract effective immune responses. Different mechanisms are postulated to explain the inefficiency of specific immunity. Thus, several subset of immune cells such as T regulatory cells (Treg) or myeloid-derived suppressor cells (MDSCs), which inhibit an immune response by influencing the activity of another cell type, have been recently shown to restrain tumor immunity through a vast array of molecular mechanisms and to promote tumor progression. Immune responses are also tightly regulated by coactivatory or coinhibitory receptors expressed by lymphocytes. Engagement of coinhibitors leads to dampening or complete lack of lymphocyte receptor signaling, resulting in suppression or termination of immune responses to antigen. The precise molecular and cellular pathways driving such aberrant interactions in human cancer and their actual implication in disease progression are still poorly understood. Therefore, in view of the different mechanisms involved in the resistance of cancer to host immune system, any attempt to understand tumor-immune system interaction must include assessment of these tumor immunosuppressive mechanisms. Our group is particularly interested in bladder carcinoma. Of interest, Bacillus Calmette-Guerin (BCG) was pioneered in the 1970s as immunotherapy for Non-Muscle Invasive Bladder Cancer (NMIBC) and is today commonly used as standard therapy for NMIBC treatment. BCG causes a strong local inflammation in the bladder wall and its therapeutic efficacy relies on a normally functioning immune system. An influx of granulocytes and mononuclear cells is induced together with a Th1 cytokine profile, maturation of DC and activation of NK cells. Virtually nothing is known on the impact of this triggering of innate immune responses on the magnitude and functional profile of adaptive immune responses at the bladder mucosal interface. However, some patients show intolerance and resistance to this treatment, thus limiting the use of BCG therapy. In order to better understand mechanisms underlying BCG treatment failure, we started to investigate the local immune response of patients with bladder carcinoma during BCG treatment. Ex vivo flow cytometry analysis of urine allows us to follow immune cell infiltration during BCG treatment. Interestingly, our preliminary results showed an infiltration of MDSCs (CD14+CD33+CD11b+HLA-DRneg/low) in some of the patients and it will be interesting to determine whether this may be predictive of treatment failure. To gather a thorough immunological signature, here we propose not only to extend our data on the frequencies and function of such regulatory cells but also of other immune cells (e.g. T cells, Treg, NK, PMN, monocytes…), which may express inhibitory receptors (e.g. BTLA, Siglecs, PD-1…) using PBMC and urine from BCG-treated patients. To complete these data a metabolomic analysis of urine will be performed in parallel. Finally, we plan to study in vitro the impact of BCG infection of bladder tumor cells or BCG-mediated inflammation on the generation of immune regulatory cells, primarily MDSC and on the expression of some inhibitory receptors (BTLA and Siglecs) and/or their ligand (HVEM and Sialic acid). Depending on the results of our ex vivo studies along BCG therapy, we may therefore focus on one or the other of immune regulatory subsets and/or inhibitory receptors. Our studies are primarily designed to address the question how BCG therapy may influence immune regulation and therefore will provide rationales for optimizing immunotherapy against bladder tumors. However, since infiltration of immune regulatory cells are key modulator of immune responses, our results will have implications not only for cancer patients but also for understanding immune mechanisms in infectious and autoimmune diseases.
Similar projects All >
Sorted by: Start Date
Project list item
Intravesical delivery of an Fc-enhanced CD40 agonist antibody for the treatment of bladder cancer

Bladder Cancer Advocacy Network to Jeffrey Ravetch, David Knorr

USD 300,000
2020 - 2022
Project list item
Epigenetic regulators of subtype plasticity in bladder cancer

Bladder Cancer Advocacy Network to John Robert Christin

USD 1,700
2020 - 2020
Project list item
Recombinant CCL2 as a novel treatment strategy for bladder cancer

Bladder Cancer Advocacy Network to Neelam Mukherjee, Robert Scott Svatek

USD 50,000
2020 - 2021
Project list item
Defining NRF2 induced tumor invasion in bladder cancer

Bladder Cancer Advocacy Network to Yuki Kita, William Youngkwan Kim, Bernard Weissman

USD 50,000
2020 - 2021
Project list item
Targeting regulatory B cells (Bregs) to improve anti-bladder cancer immunity

Bladder Cancer Advocacy Network to Burles Avner Johnson, David McConkey

USD 50,000
2020 - 2021

System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Inflammatory and Immune System

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science