Rational Design of ECMs Toward Cancer Immunotherapy

Abstract                                                      

Immunotherapies are increasingly critical to clinical cancer treatment and have been demonstrated to be a superior component of combination therapy in patient-specific precision treatment. Basic strategies have been introduced to enhance the antitumor efficiency, including augmenting the immune cell infiltration between tumor cells or increasing the immune cell activation and expansion. The importance of building a well-designed extracellular matrix (ECM)-based delivery platform that targets immune regulation could not be underestimated. The delivery platform contains the ECM-based scaffold for encapsulating selected cargo based on the targeting cancer model and therapeutic strategies. ECMs can be utilized to enhance the expansion of immune cells in vitro and in vivo so the immune response would be more robust, making cancer immunotherapy more efficient. ECMs can be optimized considering the biochemical and biophysical cues and the interactions between ECMs and immune cells. This article will discuss how ECMs can be appropriately utilized in cancer immunotherapy and discuss the possibilities and opportunities from the angle of interactions between ECMs and immune cells.

Introduction                                               

Immunotherapy strategies are incredibly critical on the road to clinical cancer treatment. Cancer immunotherapy refers to a treatment that activates or artificially optimizes the immune system to recognize and attack cancer cells.^1–4 Cancer immunotherapy provides several advantages over conventional treatment methods like surgery,⁵ radiotherapy,⁶ chemotherapy,⁷ and other drugs that directly eliminate tumor cells. These benefits include the ability to precisely target cancer cells, enhance long-term efficacy, minimize side effects in terms of both frequency and severity and have the potential for combination with other therapies. Immunotherapies commonly used by clinics involve the following strategies: cell-based immunotherapies including chimeric antigen receptor (CAR)- modified T cell therapy,⁹ CAR NK cell therapy,¹⁰ and other immune cell-based therapies; immune checkpoint blockade11–13 which is among the most frequently used cancer immunotherapy in clinical trials;¹⁴ and tumor vaccines, including human papillomavirus (HPV) and hepatitis B (HBV) vaccines.^15–17 Other infrequently used immunotherapies include cytokine therapies¹⁸ and bacterial therapies.¹⁹ In some clinical trials, immunotherapy is combined with other treatments such as radioisotope therapy,²⁰ chemotherapy,²¹ photodynamic,²² and ultrasound therapy²³ to target patient-specific diseases with optimal strategies for maximizing performance.

Furthermore, in recent years, the Food and Drug Administration (FDA) has approved various immune drugs and immune cell therapy strategies for the treatment of diverse types of cancer. For example, the HPV vaccine has been widely inoculated;²⁴ pembrolizumab has been approved for non-small cell lung cancer (NSCLC),²⁵ nivolumab and ipilimumab have been approved for renal carcinoma,²⁶ and CAR-T therapy has been approved for certain types of lymphoma and leukemia.²⁶ Moreover, the number of FDA-approved cancer immunotherapy treatments is increasing annually.^27–29

Despite its advantages, many diseases cannot be treated by immunotherapy.³⁰ For instance, cancer antigens are often not effectively delivered to immune cells, the efficiency of immune cell activation and proliferation is too low, and artificial cells (e.g., CAR-T cells) show over-immunization in clinical trials, which can threaten solid tumor patients’ lives. Meanwhile, other concerns such as safety, efficiency, accuracy, and autoimmune reactions remain to be considered.³¹ Immunosenescence,³² known as age-related alterations in the immune system, has long been a subject of discussion regarding their impact on the heightened susceptibility to cancer among the terminal cancer patients and elderly population.³³ They are also unavoidable factors. Therefore, it is important to note that the effectiveness of these strategies may vary depending on the specific type of cancer, the stage of the disease, and individual patient factors. Ongoing research and clinical trials continuously explore and refine these approaches to improve immunotherapy efficiency.

Extracellular matrices (ECM) are complex networks of proteins and polysaccharides that provide structural and biochemical support to cells and tissues. ECMs with good biocompatibility and immunogenicity can induce the maturation and expansion of immune cells and provide a way for immune regulation through their design. Engineering approaches utilizing the ECM can enhance the effectiveness of immune therapy, either directly or indirectly. By manipulating the physical and chemical properties of biomaterials, engineered ECM can serve as frameworks or injectable carriers, allowing for adjustment of the immune response and improving the effectiveness of tumor immunotherapy within the body.³⁴ In this context, we will focus on the relationships between ECMs, immune reactions, and cancer therapy, as well as the role of ECMs in enhancing cancer immunotherapy. This will encompass an examination of the material types, the strategic design of materials for controlling cancer immunotherapy through biophysical and biochemical cues, as well as the prevalent or emerging applications of biomaterials in the field.

Immunomodulatory ECMs

To further explore cancer immunotherapy, it is essential to develop appropriate ECMs that enable optimal interaction with immune cells. This involves employing fundamental strategies to enhance the immune response by adjusting the infiltration, activity, and quantity of immune cells.

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Synthetic ECMs

• Poly (lactic-co-glycolic acid) (PLGA)
• Polyvinyl alcohol (PVA)
• Polyethylenimine (PEI)
• Hydrophobic poly(beta-amino-ester) (PBAE)

Natural ECMs

• Chitosan
• Alginate
• Collagen
• Dextran
• Hyaluronic acid (HA)
• Inorganic materials

Interactions between ECM & immune cells

Immunogenicity is the prime consideration for designing the supramolecular biomaterials utilized in vivo. However, the rules for maximizing or alleviating immunogenicity in immunotherapies require further investigation.⁷⁴ Biochemical and biophysical cues from the tissue microenvironment play a crucial role in guiding immune responses and influencing the behaviors of immune cells, such as their initiation and proliferation.⁷⁵

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Biophysical Cues

• Mechanical properties
• Electrical properties
• Other external stimuli

Bio-chemical cues

• Polymer-based design
• Adjuvant
• Surface modification
• Matrix-binding / loading molecular conjugates

Applications of materials in cancer immunotherapy

In the cancer immunotherapy workflow, biomaterials can be used in vitro for immune cell culture, expansion, and activation for in vivo for drug delivery and immune cell activation. To better activate or increase the aggregation of immune cells within the tumor and decrease the off-target effects, researchers have proposed several novel strategies for enhancing the delivery process, including implantable scaffolds, injectable/spreadable hydrogels, transdermal microneedles, nanoparticles and matrix-binding molecular conjugates¹²⁰. Researchers also utilize engineered approaches to activate or screen immune cells in vivo. Herein, in vivo and in vitro applications will be discussed, respectively. (Figure 3)

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In vivo Studies

• Implantable Scaffold
• Injectable/spreadable Hydrogel-based Biomaterial
• Transdermal Microneedle

In vitro Studies

• Immune Cell Activation and Expansion
• Immunoadsorption

Conclusion & Outlook

ECMs have been demonstrated to play a crucial role in promoting the clinical application of cancer immunotherapy. Immunomodulatory ECMs can be used in vitro and in vivo to build a superiorly designed ECM-based delivery platform, promote and control immune cell behavior through ECM interactions, and ultimately improve cancer treatments. 

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