Tumor Microenvironment-Determined Resistance

Background of TME

The tumor mass is not solely comprised of a heterogeneous population of cancer cells; it also encompasses a diverse array of resident and infiltrating host cells, secreted factors, and extracellular matrix proteins, collectively referred to as the tumor microenvironment (TME). The trajectory of tumor progression is profoundly shaped by the intricate interplay between cancer cells and their environment, ultimately dictating whether the primary tumor is eliminated, spreads to distant sites through metastasis, or establishes dormant micrometastases. Moreover, the TME exerts significant influence over therapeutic responses and resistance, underscoring the recent emphasis on targeting its components, as exemplified by the notable clinical success of immune checkpoint inhibitors.

A schematic diagram of the anti-angiogenic therapy resistance. (Ma, 2018) Fig.1. Unveiling the TME's impact on anti-angiogenic therapy resistance.^1,4

The Effect Factors of TME-Determined Resistance

TME signifies a reservoir of pivotal regulators governing immune responses against cancer, encompassing both tumor cells and T-cells. Furthermore, certain regulators predominantly encompass immunosuppressive cellular elements, molecules, cytokines, and chemokines.

Immunosuppressive cells:
Within the TME, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) play pivotal roles in driving resistance to immune checkpoint inhibitors (ICBs). MDSCs hinder T cell responses through various mechanisms, impacting patient survival, while depleting intratumor MDSCs can restore the effectiveness of PD-1 blockade. Tregs and TAMs contribute to immune suppression and poor prognosis, and targeting these cells, along with strategies to reverse CAF-mediated T cell spatial distribution, holds promise for overcoming ICB resistance in cancer therapy.
Immunosuppressive molecules:
Within the TME, immunosuppressive cytokines like TGF-β released by tumors and macrophages inhibit effector T cells and promote immunosuppression, affecting cancer prognosis. Targeting TGF-β receptor kinase may enhance CTLA-4 blockade efficacy. IFNγ-induced IDO, produced by tumor and myeloid cells, suppresses effector T cell function by depleting tryptophan, potentially contributing to immune evasion. Combining IDO inhibitors with immune checkpoint inhibitors shows promise in preclinical studies, awaiting clinical validation. Other molecules like CEACAM1, adenosine, CD73, CDKs, and TIM-3 may also impact ICB resistance. Chemokines and their receptors, including CCR4, CXCR4, CCL5, CCL7, and CXCL8, mediate MDSCs and Tregs recruitment to the TME. Inhibiting these chemokine receptors could disrupt immune evasion, enhancing T cell-mediated anti-tumor responses, and offering a strategy to overcome ICB resistance.
Aberrant signaling pathway regulation:
Dysregulated PI3K/AKT/mTOR signaling impacts cellular functions and is linked to innate resistance to PD-1/PD-L1 blockade, while PTEN loss in melanoma patients contributes to immunosuppressive cytokine overexpression, affecting ICB resistance. Targeting the PI3Kβ isoform can enhance the effectiveness of PD-1/PD-L1 blockades, and activation of the Wnt/β-catenin pathway may induce T cell exclusion, leading to primary resistance to ICBs. JAK/STAT/IFN-γ and ERK/Erk MAPK pathways are also implicated in immune checkpoint inhibitor resistance, highlighting the complexity of cellular signaling pathways in modulating immune responses within the TME.

Case Study

A schematic diagram of the diverse cellular landscape of the TME. (Khalaf, 2021)

Fig.2. Illustrating the diverse cellular landscape of the TME.^2,4

The TME, encompasses diverse elements, including its vasculature, stromal components, immune cells, and extracellular matrix, fostering an immunosuppressive and nutrient-deprived milieu essential for tumor growth, adaptation, and resistance to therapies. Cellular crosstalk and cell-to-ECM communication within the TME drive the release of soluble factors, facilitating immune evasion and ECM remodeling, further exacerbating resistance to treatment. Factors such as exosomes, deregulated microRNAs, TME-specific metabolic patterns, hypoxia, metabolic dysregulation, and mechanical forces contribute to treatment resistance, making the TME a pivotal focus in understanding and combating therapy resistance.

A schematic diagram of the TME. (Jin, 2020)

Fig.3. Revisiting the evolving terrain of the TME.^3,4

TME has emerged as a critical factor in shaping tumor behavior and responses to therapies, shifting the focus of cancer research and treatment from the tumor itself to the TME. Despite this shift, the clinical effectiveness of TME-targeted therapies remains limited, emphasizing the need for a better understanding of TME characteristics and interactions among its components to develop more potent treatment approaches. This comprehensive review delves into various facets of the TME, including hypoxia, immune responses, metabolic influences, acidity, neural connections, and mechanical factors, while also exploring the potential repurposing of conventional drugs for innovative anti-tumor applications, offering valuable insights into the future of TME-driven cancer treatment strategies.

Services

Creative Biolabs offers an extensive array of customized services related to immune checkpoints, which include but are not limited to: Immune Checkpoint Antibody Development, Immune Checkpoint Assays, Immune Checkpoint Targeted Peptide Development, etc. Please contact us for a thorough understanding.

References

Ma, Shaolin, et al. "The role of tumor microenvironment in resistance to anti-angiogenic therapy." F1000Research 7 (2018).
Khalaf, Khalil, et al. "Aspects of the tumor microenvironment involved in immune resistance and drug resistance." Frontiers in immunology 12 (2021): 656364.
Jin, Ming-Zhu, and Wei-Lin Jin. "The updated landscape of tumor microenvironment and drug repurposing." Signal transduction and targeted therapy5.1 (2020): 166.
Under Open Access license CC BY 4.0, without modification.

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