From Barrier to Opportunity: Unlocking the Tumor Microenvironment

The saying goes that no man is an island, and as it turns out, neither is cancer. Tumors are surrounded by a complex non-cancerous ecosystem containing immune, stromal, and vascular cells, diverse cytokines, and immune checkpoints.¹ Scientists have discovered that this tumor microenvironment (TME) plays a crucial role throughout cancer development, from initiation to metastasis. Developing tumors can distort immune cell signaling to drive chronic, damaging inflammation, which promotes both tumor progression and resistance to therapy.^1,2 The TME also supports tumoral immune evasion. Myeloid cells, for example, can secrete mediators such as IL-10 and TGF-β to inhibit T cells and natural killer cells, trigger inflammation via the release of IL-1β, TNF-α, and IL-6, and express PD-L1, a checkpoint ligand that prevents immune cells from identifying and eliminating cancer cells.¹

The TME Presents Experimental Challenges and Scientific Opportunities

It is perhaps no surprise that preclinical cancer models that fail to consider the TME show limited success in therapeutic development. Subcutaneous cell line-derived xenograft (CDX) models, in which scientists inject human cancer cell lines below a mouse’s skin, are a case in point.³ CDX models do not recapitulate the TME of the tumor’s organ of origin, and the US Food and Drug Administration has only approved 3-5 percent of the cancer drugs developed using these models. Taking the complicated, dynamic TME into account when developing immunotherapies and preclinical cancer models is no easy feat, but it may usher in new, paradigm-shifting discoveries.

One of the hurdles to studying the TME is the trade-off between complexity and controllability that is broadly inherent to cancer models.³ In vivo models more faithfully recapitulate the TME but are difficult to manipulate, while simpler in vitro models can be subjected to minute experimental perturbations but do not fully capture the TME’s complexity and heterogeneity. Enter functional antibodies, which can precisely target the TME in both in vivo and non-animal models to facilitate the discovery of novel immunotherapies and deepen scientific understanding of this intricate ecosystem.

Functional Antibodies Are an Indispensable Tool for Modulating the TME

Bio X Cell’s ready-made functional antibodies are widely used by the research community to investigate and manipulate the TME, with thousands of peer-reviewed publications demonstrating their significance in cancer biology. The company’s cancer biology portfolio includes hundreds of functional antibodies scientists can use to deplete, modulate, or block the cells, cytokines, and immune checkpoints comprising the TME. This allows Bio X Cell to support diverse experimental strategies, including depleting regulatory T cells with anti-CD25, targeting myeloid-derived suppressor cells with anti-Gr-1, and modulating macrophage activity using anti-CSF1R. Additionally, researchers can block cytokine pathways with anti-TGF-β or anti-IL-10R and activate co-stimulatory signaling with agonists such as anti-4-1BB or anti-CD40.

Immune checkpoints such as anti-mPD-1 and anti-mCTLA-4 are also intriguing targets for cancer researchers, as in the case of Yumeng Wang and her group at Fudan University.⁴ Wang and her team wanted to understand how signaling between the TME and innate immune cells establishes immune tolerance, and they were particularly interested in dendritic cells (DCs), which can mediate immunosuppression in cervical cancer. The Siglec family of receptors typically acts as immune checkpoints, and Wang’s group found that cervical cancer cells push DCs in the TME toward a low-immunogenicity, high-immunotolerance phenotype via sialoglycan/Siglec-10 signaling. The team found that blocking Siglec-10 in a patient-derived tumor fragment platform enhanced DC-mediated tumor cell apoptosis. However, adding a Bio X Cell anti-PD-1 antibody to the Siglec-10 blockade drove an even greater mobilization of the immune system against the tumor. These results highlight the power of synergistically blocking multiple immune checkpoints and could lead the way to new cervical cancer immunotherapies.

While Wang and her team surely had their share of experimental challenges, the reliability of their anti-PD-1 antibody was not one of them: like all of Bio X Cell’s antibodies, its functional activity was verified in living systems. Bio X Cell’s antibodies are ideal for sensitive in vivo and in vitro experiments thanks to their purity, extremely low endotoxin levels, and preservative- and stabilizer-free formulation. With high-quality, validated functional antibodies in their toolbelt, cancer researchers can begin to unravel the mysteries of the TME.