Biophysical Control of the Glioblastoma Immunosuppressive Microenvironment: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Joseph Chen.

Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer with a dismal prognosis. Current GBM treatments have not improved patient survival, due to the propensity for tumor cell adaptation and immune evasion, leading to a persistent progression of the disease. In recent years, the tumor microenvironment (TME) has been identified as a critical regulator of these pro-tumorigenic changes, providing a complex array of biomolecular and biophysical signals that facilitate evasion strategies by modulating tumor cells, stromal cells, and immune populations. Efforts to unravel these complex TME interactions are necessary to improve GBM therapy. Immunotherapy is a promising treatment strategy that utilizes a patient’s own immune system for tumor eradication and has exhibited exciting results in many cancer types; however, the highly immunosuppressive interactions between the immune cell populations and the GBM TME continue to present challenges.

  • glioblastoma
  • immunotherapy
  • tumor microenvironment
  • biophysics

1. Introduction

Glioblastoma (GBM) is the most aggressive and common type of primary brain cancer. The median patient survival is only 15 months, and the 5-year survival of 5–7% remains one of the lowest among cancer types [1,2,3,4,5][1][2][3][4][5]. This poor prognosis remains despite aggressive treatment via surgical resection, radiotherapy, and chemotherapy [6,7][6][7]. GBM progresses as a result of pro-malignant physical and chemical factors in the TME that promote therapy resistance, immune evasion, and rapid tumor dissemination throughout the brain. This ultimately leads to an incomplete elimination of the GBM cells, which seed and generate more aggressive, secondary tumors [8,9,10,11][8][9][10][11] that reduce survival and quality of life [11,12,13][11][12][13].
Immunotherapies represent a paradigm shift in cancer therapy, leveraging an individual’s own immune cells to eliminate the cancer cells. This has proven to be effective in a wide range of cancer types and provides hope for GBM treatment [16,17,18,19,20,21][14][15][16][17][18][19]. In a healthy human body, the host’s immune system will naturally work to eliminate cancer cells, most often via natural killer (NK) cells [22,23,24,25,26][20][21][22][23][24] and T cells [24[22][24][25][26][27],26,27,28,29], but macrophages have also been implicated in possessing a small tumoricidal capacity, although they more often adopt a protumorigenic phenotype [26,30][24][28]. These cells utilize many pathways and mechanisms to eliminate cancerous cells before they aggregate and develop a tumor. Despite the overall efficiency of these mechanisms, some cancer cells can shift their phenotypes, release immune-cell-suppressing signals, and alter the surrounding extracellular matrix (ECM) to increase tumor survival. Thus, the basic rationale for immunotherapy is to equip immune cells with new molecular tools to identify and successfully eradicate cancerous cells. However, despite the overwhelming success of immunotherapy, its effectiveness is not universal and depends largely on the TME of different tumors. Tumors such as GBM are labeled as immunoevasive or “cold tumors” and have less immune cell infiltration [31,32,33][29][30][31]. Such changes associated with GBM include the adaptation of surface receptors to limit immune cell binding [34,35][32][33], the reprogramming of immune cells such as parenchymal macrophages (microglia) and neutrophils to more protumorigenic profiles [36[34][35][36][37][38][39],37,38,39,40,41], and the recruitment of inhibitory immune cells such as regulatory T cells (Tregs) [42,43][40][41] and myeloid-derived suppressor cells (MDSCs) [44,45,46][42][43][44], which secrete immunosuppressive cytokines such as TGFβ, IL-10, and IL-35 [47,48,49][45][46][47]. Together, these factors reduce the amount of tumoricidal immune cell infiltration and generate protumorigenic/anti-immune signals to create a highly immunosuppressive microenvironment.

2. Biophysical Aspects of the TME

2.1. ECM Composition

Solid tumors comprise a wide range of highly expressed ECM proteins that include laminins, fibronectin, elastin, and fibrillar collagen [63][48]. These proteins provide functionality and stability to the tumor environment for disease progression and accounts for up to 60% of the tumor mass [64][49]. Indeed, the presence of these proteins plays a key role in regulating the pro-invasion and therapeutic resistance within the tumor that help to direct cell migration, adhesion, and proliferation similar to that seen in early development [65][50]. Several ECM proteins of interest in GBM have been identified over the last several years including osteopontin, hyaluronic acid (HA), and laminin and are known to increase invasion potential through mechanotransduction signals transmitted throughout the cytoskeleton [66,67,68][51][52][53]. Further, HA is the primary ECM component in the brain, and it has been strongly implicated in GBM tumor development and depends on the HA molecular weight—high-molecular-weight HA has an anti-tumor effect and low-molecular-weight HA has a pro-tumor effect [67,69,70,71,72][52][54][55][56][57].

2.2. ECM Mechanics

Besides ECM composition, the mechanics of the ECM can direct cell behavior [73][58] and tumor malignancy. Increased substrate stiffness has been shown to increase proliferation and single-cell migration in GBM. ECM stiffness can also increase cell adhesiveness, which interestingly reduces collective migration due to dense networks of cell–substrate adhesions [74,75][59][60]. These stiffnesses also affect the density of the matrix and can facilitate primary tumor escape during metastasis [76][61] by providing permissive porous environments to increase cell escape from the tumor or inhibitory dense environments that would confine the cell to the tumor.

2.3. Interstitial Fluid Flow

The increased mechanics of the intratumoral space caused by the high stiffness and density can also affect the flow of interstitial fluid throughout the tumor. The flow of interstitial fluid through the tumor exposes the cells to fluid pressure and soluble cues such as pro-angiogenic factors and anti-inflammatory TGF-β1 signals [79][62]. These factors function to inhibit anti-tumor immune cells and promote pro-tumor immune cells by maintaining the inflammation of the tumor to a sustainable level.

3. Biophysical TME-Immune Cell Interactions

It has been established that the biophysics of the TME and ECM can regulate cell behavior in a pro-tumorigenic capacity. However, besides cancer cells, other types of cells including the immune cell populations are regulated by the biophysical TME (Figure 1).
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Figure 1. Biophysical properties reduce immune cell–cancer cell interactions. Within the TME, many biophysical cues work together to create an immunosuppressive environment. Substrate stiffness reduces the migration capacity of T cells and limits the tumoricidal capacity of CD8+ cells (A); intratumoral pressure transforms macrophages into a tumor-supportive phenotype that produces anti-inflammatory cytokines that inactivate infiltrating T cells and recruits regulatory T cells (B); and dense tumor tissue alters cell shape and cytoskeletal organization and limits the chance of antigen recognition (C).

3.1. Substrate Stiffness

Healthy and cancerous somatic cells can be characterized by their degree of mechanosensing and mechanotransduction. Generally, stiffer substrates correspond to greater cell migration due to increased contractility [83,84,85,86][63][64][65][66]; yet, for the immune cells, the effect is less pronounced with respect to cell migration (Figure 1A). Dendritic cells are a type of antigen-presenting cell that helps link the innate and adaptive immune systems by presenting an antigen to a lymphocyte such as a T cell to induce recognition and a response against the tumor cells [87][67]. During improper antigen presentation, the T cells are unable to effectively recognize and eliminate the source of the antigen.

3.2. Intratumoral Pressure

In a similar manner to the stiff tumor, an interstitial fluid flow induces pro-tumorigenic effects on the immune cells in the TME (Figure 1B). Tumors often utilize the lymphatic system to invade and metastasize [99][68]. This system specializes in fluid drainage and, therefore, it is not uncommon to find heightened pressure gradients at the junction of tumor and lymphatics. These junctions experience an increased flow and mechanical stress, which serves to cause DNA damage and increase the production of cytokines such as TGF-β1 to reduce inflammation [99,100,101][68][69][70]. Furthermore, the interstitial pressure is sufficient to induce a pro-tumorigenic macrophage phenotype as seen by the upregulation of M2 macrophage markers ArgI, TGM2, and CD206 [102][71]. This development of M2 macrophages further works to inhibit T cell function via the additional TGF-β1 production and expression of immune checkpoint ligands that inactivate infiltrating T cells [103,104][72][73].

3.3. Confined Migration

Considering the density of the brain parenchyma, it is unsurprising that GBM is an innately aggressive cancer. For many cell types, migration in a confined environment can lead to DNA damage via nuclear rupture [104][73], which serves as the basis for the development of metastatic cancer [111][74]. During infiltration of the TME, the immune cells will enter a state of confined migration (Figure 1C). Macrophages have been observed to form a protective actin cortex that shields against compressive forces that can damage the nucleus and lead to cell death [112][75]. This enables a more efficient and safe form of migration necessary for patrolling throughout the confined environments. Likewise, T cells navigate a variety of confined spaces as they patrol throughout the body; however, while patrolling, the T cells also interact with antigen-presenting cells. This presents a balance that must be maintained between migrating quickly through an environment and spending enough time in the same location as the antigen-presenting cell to become activated against an antigen [113][76].

4. Bioengineering Systems

4.1. Biomaterial Systems

Biomaterials are synthetic or natural materials that can be engineered to mimic physiological and pathological environments and are foundational to investigate cell-ECM interactions. Among the most common biomaterials are hydrogel-culture-based systems due to their versatility in controlling factors such as stiffness, ECM composition, and other biomolecules such as growth factors [122][77]. In the context of solid tumors such as GBM, the most important immune cell functions to consider are tumor infiltration and tumor cell elimination. Hydrogel-based platforms have proven vital in dissecting the interplay between immune cells and the tumor ECM. The mechanosensing capacity of T cells has been interrogated via TCR-mediated activation through the introduction of HA binding [123][78] and the tuning of the stiffness to biomimetic levels [123,124][78][79].

4.2. Microfabrication

Microfabrication approaches such as 3D printing and microfluidics represent important tools for studying the contribution of geometric cues as well as observing cell phenomena in a single-cell context. Many studies leverage these tools to decipher the migration mechanisms of immune cells. In the 3D context, CD8+ T cell amoeboid migration operates through a contractility driven mechanism via RhoA activation that is unique to the 2D environment [129,130,131][80][81][82]. Additionally, the T cell transfection efficiency can be modified on microfluidic systems through mechanoporation via stretching to engineer T cells with greater motility, antigen recognition, and antigen elimination [132,133][83][84].

4.3. Advanced In Vitro Systems

Creating more complex, biologically relevant in vitro systems serves as an intermediate step before reaching in vivo models. Co-culture models combine multiple cell types into a single culture environment to analyze real-time interactions between the cells, and lab-on-a-chip technology is useful for combining multiple physiological systems to determine how cell processes differ between the environmental changes. Macrophages and microglia are normally susceptible to reprogramming via GBM cues that promote tumor development; yet, when cultured separately, these changes cannot be observed. Therefore, co-culture systems allow for the necessary paracrine and juxtacrine interactions (ephs/ephrins [137][85] or P-selectin/PSGL-1 [138][86]) involved in the bidirectional communication between the tumor and immune cells to occur and be observed. These interactions are intended to help recognize the cancer cells for immune-cell-mediated elimination but are often dysregulated to instead promote tumor survival and development.

5. Immunotherapy Applications

From the mechanistic insights gained through bioengineering systems, researchers can leverage these interactions to optimize immunotherapy protocols to increase efficacy and improve patient survival. By engineering the culture expansion platforms of immune cells and the activities of immune cells, efforts to increase the tumoricidal capacity of immune cells are growing. In recent years, many types of cancers have seen significant improvement due to the development of novel immunotherapies, their developments in treating GBM, and the biophysical design of the therapies (Figure 2).
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Figure 2. Bioengineering systems improve cancer immunotherapy strategies. Bioengineering systems added into the immunotherapy pipeline can offer enhanced propagation of CD8+ T cells and increased CAR-T generation. Cell culture platforms containing native ECM components that are tuned to physiologically relevant stiffnesses increase CD8+ T cell propagation. (A). Microfluidic systems can be designed to increase CAR-T transfection efficiency via serial physical compression, called mechanoporation. Top and cross-sectional views are presented in (a) and (b), respectively. This high-throughput strategy elevates transfection efficiency while maintaining cell viability, offering marked improvements that can be easily integrated into the CAR-T workflow (adapted from [132][83]) (B).

5.1. Tunable Hydrogel Culture Systems

ECM composition and mechanics are involved in determining the degree of functionality of not only cancer cells but immune cells as well. For GBM treatments, studies have been conducted that utilize HA due to the ease with which it can be modified without sacrificing material characteristics [142,143][87][88]. This degree of tunability has proven useful by helping to expand and activate T cells that are otherwise limited by the relatively slow growth and loss of characteristic phenotypes in traditional culturing methods (Figure 2A). HA gels are easily conjugated with signals necessary to activate T cells in greater magnitudes than with soluble signal presentation [141][89].

5.2. Chimeric Antigen Receptor Therapy

In addition to the removal and reintroduction of cells following the ex vivo differentiation into an anti-tumor phenotype, the direct modification of immune cells has also had success in treating various types of cancers. The generation of chimeric antigen receptors (CARs) for T cells involves removing T cells from a patient and using gene engineering to induce the production of a single type of synthetic receptor for antigen recognition [149,150][90][91]. To increase successful T cell transfection, microfluidic systems have stretched cells to increase membrane pore formation, which allows for greater mRNA entry to generate the CAR (Figure 2B) [132,133][83][84].

5.3. Checkpoint Blockade

Another therapy option utilized in even more cancers is the use of immunologic checkpoint blockades. This therapy uses antibodies to inhibit the programmed death of T cells induced by the binding of PD-1 or to prevent the activation of the T cell via CTLA-4 [160,161,162][92][93][94]. These receptors naturally become activated to prevent T cell overactivity; however, cancer cells can trigger these pathways as well to limit T cell-mediated tumor killing through the reduction in cytokine and granule production. To prevent this inhibition, antibodies are developed that are specific to either the tumor cell (PD-L1) or the T cell (PD-1/CTLA-4) and are administered [160,161,162,163][92][93][94][95]. The type of antibody used and its receptor target are variable depending on the state of the tumor and the effectiveness in promoting T cell activity.

6. Conclusions

GBM is an extremely deadly type of brain cancer that has remained difficult to treat in part due to its high resistance to standard therapies and immunotherapy. The dynamic TME is a key driver of cancer progression and presents pro-malignant biophysical signals including ECM composition, density, stiffness, and interstitial fluid flow, which helps direct the flow of soluble cues, increases the intertumoral pressure on the cells, and generates hypoxic regions. Ultimately, these factors work together to promote tumor growth and disease progression; however, these factors also dysregulate immune cells through the production of immunosuppressive cytokines, the recruitment of inhibitory immune cells, and/or the conversion into tumor-supportive tumor-associated immune cells. Biomedical research has made strides in elucidating the underlying mechanisms of the biophysical TME on immunosuppression through novel bioengineered tools and platforms. The insights gained have been eagerly applied to bolster immune cell expansion techniques and enhance immunotherapy through the biophysical manipulation of the ECM and immune cell receptor manipulation.

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