Immunomodulation strategies for the tumor microenvironment and type I diabetes
Embargo Date
2027-03-11
OA Version
Citation
Abstract
The mammalian immune system encompasses a complex network of different cell types and signals, for which proper function requires the correct identification of agents as either “self” or “non-self”, and harmful or harmless, and an appropriate response for each. To communicate among different immune cell types and organize responses to potential threats to the body, the immune system utilizes signaling molecules, known as cytokines. However, cancers can manipulate the immune system both through their identity as “self”, and through cytokine signals that suppress potential immune system responses. Additionally, the immune system can mistakenly identify self-antigens as non-self or harmful, which can trigger autoimmune attack in diseases such as Type I Diabetes.In cancer, tumor cells shape their microenvironment with different signals in order to survive, proliferate, and evade immune system responses. One such signal involves interleukin-4 (IL-4), an immune suppressive cytokine that induces polarization of macrophages to the M2 phenotype. M2 macrophages, known as tumor-associated macrophages (TAMs) in the tumor microenvironment (TME), further temper potential immune responses against the tumor through the expression of additional immunosuppressive cytokine signals. Herein, the use of the novel small molecule inhibitor of IL-4, Nico-52, is investigated for potential tumor suppressive properties in the melanoma model of B16-F10 tumor-bearing Black6 mice. Nico-52 and its analogues exhibited favorable pharmacokinetic properties in in vitro ADME/T assays, such as high stability and low cytotoxicity. Nico-52 treatment in vivo also demonstrated tumor suppressive effects and increased survival in B16-F10 and 4T1 tumor-bearing Black6 mice.
The prevalence of Type I Diabetes has been increasing world-wide, particularly in North America and Europe, and current treatment options are mainly limited to glucose monitoring and costly lifelong insulin injections. The autoimmunity that causes Type I Diabetes is linked to a loss of central tolerance in the thymus. In central tolerance, medullary thymic epithelial cells (mTECs) present tissue-specific antigens (TSAs) to developing T cells to identify and negatively select autoreactive cells. However, loss of expression of the transcription factor autoimmune regulator (AIRE) causes central tolerance to fail, which allows autoreactive T cells to further develop. This loss of central tolerance has been indicated in the NOD disease model of Type I Diabetes. As a potential treatment, epigenetic modulating compounds were examined as a means of restoring AIRE expression in mTECs and rescuing central tolerance. Romidepsin, an HDAC inhibitor, was identified as a lead candidate for restoration of AIRE expression. The compound was shown to increase the expression of AIRE in ex vivo thymus experiments, with a greater effect in NOD Type I Diabetes disease model mice. However, it failed to have a therapeutic effect in NOD mice with systemic in vivo administration, likely due to inefficient biodistribution to the thymus and indiscriminate effects on different tissues.
The failure to achieve therapeutic results in vivo is not uncommon in drug development. While a therapy can have potent effects in in vitro models, inefficient biodistribution in vivo is a major hurdle to achieving necessary efficacy and safety. For anti-cancer agents, tumor heterogeneity leading to acquired drug resistance (ADR) is a common factor in their failure, even though tumors can exhibit enhanced permeability and retention (EPR) of drugs. Additionally, some tissue targets like the thymus are more challenging to achieve distribution to than others, such as the liver.
Therefore, tissue specific targeting strategies are being explored to deliver therapies to their targets more efficiently. Near-infrared fluorescent probes enable tissue-specific visualization of the biodistribution of potential targeting agents that can be utilized for thymus targeted treatments. Further, the use of lanthanide metal probes with the highly specific and sensitive detectors in mass cytometry (CyTOF) may potentially allow for measuring biodistribution on the cellular level within tissues.
Description
2024
License
Attribution 4.0 International