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Related Concept Videos

The Tumor Microenvironment02:17

The Tumor Microenvironment

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Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
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Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
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Related Experiment Video

Updated: Dec 28, 2025

Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
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Checkpoint molecules coordinately restrain hyperactivated effector T cells in the tumor microenvironment.

Min Yang1,2, Wenwen Du2,3, Lixian Yi2,4

  • 1Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou China.

Oncoimmunology
|February 21, 2020
PubMed
Summary

Immune checkpoint blockade (ICB) therapy shows promise but has low response rates. Targeting multiple checkpoints like PD-1, Tim-3, and Lag-3 simultaneously enhances anti-tumor activity by overcoming immune resistance in cancer.

Keywords:
Lag-3PD-1Tim-3combination therapyexhaustiontumor immunotherapy

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Area of Science:

  • Immunology
  • Cancer Biology
  • Immunotherapy

Background:

  • Immune checkpoint blockade (ICB) immunotherapy improves cancer patient survival but faces low response rates.
  • Resistance to ICB is often linked to compensatory upregulation of additional immune inhibitory molecules.

Purpose of the Study:

  • To investigate the expression of T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) in immune cells within the tumor microenvironment (TME).
  • To evaluate the efficacy of combined blockade of multiple immune checkpoints in a mouse cancer model.

Main Methods:

  • Systematic examination of Tim-3 expression in various immune cells (Treg, CD4+, CD8+ T cells, DC1, M1) in mouse tumors.
  • Phenotypic and functional analysis of Tim-3+ T cells.
  • Assessment of combination therapy using monoclonal antibodies (mAbs) against PD-1, Tim-3, and Lag-3.

Main Results:

  • Tim-3 was upregulated in multiple immune cell types within the TME.
  • Tim-3+ CD8+ T cells exhibited effector, not exhausted, phenotypes with higher metabolic activity and cytolytic function.
  • Combination therapy with anti-Tim-3 and anti-PD-1 mAbs showed synergistic antitumor effects and increased Lag-3 and GITR expression.
  • Triple combination therapy (anti-Tim-3, anti-PD-1, anti-Lag-3 mAbs) demonstrated significantly greater antitumor efficacy than dual combinations.
  • Simultaneous blockade of Tim-3, PD-1, and Lag-3 enhanced granzyme B levels and CD8+ T cell cytolytic activity.

Conclusions:

  • Multiple immune checkpoint molecules are coordinately upregulated in the TME to inhibit T cell function.
  • Simultaneous blockade of PD-1, Tim-3, and Lag-3 is required for effective cancer treatment, overcoming resistance mechanisms.