Modulatory Effect of Prodigiosin or Pioglitazone on Tumor Immune Microenvironment and the Crosstalk to Immune-Checkpoint Protein(s)

1. Introduction 1.1. Background Components of the tumor microenvironment (TME) presented by immune cells, tumor cells, and their derived factors are known as Tumor immune microenvironment (TIME). Tumors can gradually shape TIME into an immunosuppressive state to hinder host immunity. Two opposing immune responses help shape TIME. One side of the immune cells represented by M1 macrophage, T-lymphocyte, Dendritic cells (DC), and Natural killer cells (NK) play a role in the antitumor immune response. On the contrary, tumor-promoting immune cells represented by regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), M2 macrophage, and group 2 innate lymphoid cells (ILC2) contribute to an immunosuppressive microenvironment.

Under physiological conditions, several immune checkpoint proteins (ICPs) are expressed on various immune cells. These ICPs bind to their complementary ligand to activate T-cells' inhibitory signals, therefore they act as gatekeepers for normal cells. Among the first immune checkpoint proteins discovered were cytotoxic T-lymphocyte antigen number 4 (CTLA-4) and programmed cell death protein 1 (PD-1).. Recently, several immune checkpoint proteins have been discovered; T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), B and T cell lymphocyte attenuator (BTLA), lymphocyte activation gene (LAG3) and V-domain Ig suppressor of T cell activation (VISTA). Unfortunately, tumor and tumor-promoting immune cells exploit these ICPs to escape immune system-mediated cell death.

Several factors could control the expression of ICPs. HSP90 chaperone function plays a role in the regulation of immune cell function by controlling ICPs expression. Zavareh and his colleagues showed that HSP90 inhibitors have a direct inhibitory effect on the expression of ICPs including PD-L1 and PD-L2. Only one study implicated prodigiosin inhibitory effect on HSP90, yet, the effect of prodigiosin on novel immune checkpoint proteins and its modulatory effect on TIME via HSP90 has not been investigated.

The expression of ICPs has also been shown to be controlled by the IL-6/JAK2/STAT3 pathway. High levels of STAT3 and JAK2 levels have been attributed to poor prognosis in non-small cell lung cancer (NSCLC) patients. c-MYC, one of the downstream targets of IL-6/STAT3 signaling, could promote tumor immune escape by increasing the levels ICPs . Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, inhibited c-MYC-mediated immune escape by inducing PD-L1 protein degradation. Pioglitazone could enhance cancer immunotherapy and T-cell activation by decreasing PD-L1 protein levels . The inhibitory effect of pioglitazone on STAT3 has been studied in different types of cancer . However, the modulatory effect of pioglitazone on novel ICPs via the IL-6/STAT3 pathway and c-MYC remains to be investigated.

1.2. PROBLEM. 1.2.1.Lung Cancer is the leading cause of cancer death in both men and women aged 50 years and older. The response rate to current ICIs used for the treatment of lung cancer is far from satisfactory.