Various components of the tumor microenvironment (TME) play a critical role in promoting tumorigenesis, progression, and metastasis. One of the primary functions of the TME is to stimulate an immunosuppressive environment around the tumor through multiple mechanisms including the activation of the transforming growth factor-beta (TGF-β) signaling pathway. Cancer-associated fibroblasts (CAFs) are key cells in the TME that regulate the secretion of extracellular matrix (ECM) components under the influence of TGF-β. Recent reports from our group and others have described an ECM-related and CAF-associated novel gene signature that can predict resistance to immune checkpoint blockade (ICB). Importantly, studies have begun to test whether targeting some of these CAF-associated components can be used as a combinatorial approach with ICB. This perspective summarizes recent advances in our understanding of CAF and TGF-β-regulated immunosuppressive mechanisms and ways to target such signaling in cancer.

High-affinity ligands, such as protein A, can be used to develop biocompatible matrices for antibody purification. In this paper, two methods were used for immobilization of protein A on the chitosan. In the first approach, amino groups of chitosan beads were functionalized with tris(2-aminoethyl)amine to produce amine double-branched moieties, which were subsequently activated with glutaraldehyde. In the second approach, chitosan beads were directly modified by glutaraldehyde to produce aldehyde groups. Structural characterization and successful modification of the functional groups on the supports were confirmed by scanning electron microscopy, FTIR spectroscopy and elemental analysis. Covalent immobilization of protein A was then performed on the surface of both supports. The immobilization yield was determined by using fluorescence spectroscopy, showing almost 15% increased capacity for the double-branched derivatized chitosan. The Immunoglobulin G (IgG) purification ability of the double-branched support was also almost 1.7-fold higher than the monoaldehyde derivative at the same condition.

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

Hepatocellular carcinoma (HCC) is one of the leading cancer-related deaths worldwide. Recently, studies for HCC treatment are focused on cancer immunotherapy, particularly cancer vaccines, to complete and assist other therapies. TPX2 is a microtubule-associated protein necessary for cell division; therefore, alteration in its expression, especially up regulation, is associated with several human carcinomas such as HCC. In this study, immunoinformatics tools were used to design a rational multi-epitope T vaccine against TPX2 in HCC. Cytotoxic T lymphocytes (CTL) and Helper T lymphocytes (HTL) epitopes were predicted and Maltose-binding protein (MBP) was added to the construct as an adjuvant. Evaluation of vaccine properties was indicated that our construct is stable and immunogenic enough to induce relevant responses besides not being allergic. After predicting the tertiary structure and energy minimization, protein-protein docking was performed to calculate the free energy of possible interactions between the vaccine and toll-like receptor 4 (TLR4) to assure that simultaneous complementary responses would be activated by our construct. Finally, Codon optimization and in-silico cloning were performed to ensure the vaccine expression efficiency in the desired host.