Synthetic Matrix Scaffolds Engineer the In Vivo Tumor Immune Microenvironment for Immunotherapy Screening

Abstract

breast cancer (TNBC), which lacks hormone receptor and excess HER2 protein expression, is the most aggressive type of breast cancer, with higher rates of metastasis and shorter overall survival. [3] Immunotherapies have emerged as one of the most promising tools in the fight against breast cancer. However, response rates in the clinic are disappointingly low-only ≈16% of patients respond to immune checkpoint blockade (ICB) therapy, [4] and no vaccine therapies have been approved for breast cancer, despite successes in melanoma and prostate cancer. [5,6] These poor outcomes reflect an unmet need in understanding the differences in patient responses and tools to develop new and better immunotherapeutic strategies for patients who are less likely to respond to immunotherapies.Substantial efforts in the immune oncology field are currently dedicated to unraveling the determinants of the anti-cancer immune response, given its role in disease progression and response to immunotherapy. Immunologically "hot" tumors generally have more immune infiltration, while "cold" tumors harbor fewer immune cells. [7] Additionally, other stratifications have been identified, with the potential to influence immunotherapy responses-among immune-infiltrated (hot) tumors, macrophages, and CD8 T cells have been shown to have opposite impacts on patient survival, and in turn on Immunotherapy has emerged as one of the most powerful anti-cancer therapies but is stymied by the limits of existing preclinical models with respect to disease latency and reproducibility. Additionally, the influence of differing immune microenvironments within tumors observed clinically and associated with immunotherapeutic resistance cannot be tuned to facilitate drug testing workflows without changing model system or laborious genetic approaches. To address this testing platform gap in the immune oncology drug development pipeline, the authors deploy engineered biomaterials as scaffolds to increase tumor formation rate, decrease disease latency, and diminish variability of immune infiltrates into tumors formed from murine mammary carcinoma cell lines implanted into syngeneic mice. By altering synthetic gel formulations that reshape infiltrating immune cells within the tumor, responsiveness of the same tumor model to varying classes of cancer immunotherapies, including in situ vaccination with a molecular adjuvant and immune checkpoint blockade, diverge. These results demonstrate the significant role the local immune microenvironment plays in immunotherapeutic response. These engineered tumor immune microenvironments therefore improve upon the limitations of current breast tumor models used for immune oncology drug screening to enable immunotherapeutic testing relevant to the variability in tumor immune microenvironments underlying immunotherapeutic resistance seen in human patients.

Engineering Biomaterials to Model Immune‐Tumor Interactions In Vitro

“…Bioactive peptides conjugated to a polymer backbone enhance cellular interactions and help to chemically define the TME. For example, monofunctionalized binding peptides enhanced cell viability and proliferation of leukocytes [ 49 ] and macrophages, [ 50 ] and increased macrophage invasion in synthetic scaffolds. [ 51 ] The most commonly used peptide is arginine‐glycine‐aspartic acid (RGD), which is the principal integrin binding domain of a plethora of glycoproteins present in the TME, including collagen, fibronectin, laminin, and vitronectin.…”

Gelation Kinetics and Mechanical Properties of Thiol‐Tetrazole Methylsulfone Hydrogels Designed for Cell Encapsulation

“…To serve as artificial matrices for 3D cell culture, PEG hydrogels need to be biofunctionalized with cell-adhesive moieties such as the RGD peptide. [14,15] In our system, thiolated bioactive molecules can be incorporated into the gel network by preincubation with the PEG-4TzMS pre-polymer. This step consumes reactive sites, and is expected to affect t 50Pa and G' 40min values by decreasing the concentration of MS groups available for crosslinking.…”

Bioresponsive Self‐Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune‐Related Adverse Events in Tumor Immunotherapy

“…[ 12 ] On the other hand, the intricate immunosuppressive tendency of the tumor microenvironment (TME) should also be considered as an important reason for poor patient response rate to therapy. [ 15 ] Notably, most resident immune cells other than tumor cells in the TME are tumor‐associated macrophages (TAMs), which are among the most important “editor” of the TME. [ 14 ] There are two transferable states of TAMs, activated or inflammatory macrophages (the M1‐like phenotype) and alternatively‐activated or anti‐inflammatory macrophages (the M2‐like phenotype).…”