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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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Close Spatial Interactions between Cancer Cells and Cancer-Associated Fibroblasts Suppress Antitumor Immunity.

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Cancer-associated fibroblasts (CAFs) close interactions with cancer cells suppress antitumor immunity more than physical barriers. Targeting these interactions and periostin may enhance cancer immunotherapy efficacy.

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Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Cancer-associated fibroblasts (CAFs) are known to suppress antitumor immunity within the tumor microenvironment.
  • Their role as physical barriers to immune cell infiltration is established, but their precise spatial relationship with cancer cells and its impact on immunity is unclear.

Purpose of the Study:

  • To investigate the impact of spatial relationships between CAFs and cancer cells on antitumor immunity.
  • To explore the underlying molecular mechanisms and therapeutic potential of targeting CAF-cancer cell interactions.

Main Methods:

  • Utilized 3D bioprinting to create controlled spatial constructs of fibroblasts (FB) and cancer cells.
  • Analyzed the effects of mixed vs. surrounding FB distribution on antitumor immunity in vitro and in vivo.
  • Investigated TGFβ and periostin (Postn) cross-talk and the impact of Postn knockdown.
  • Correlated CAF distribution patterns with patient prognosis and immune cell infiltration in head and neck and lung cancer.

Main Results:

  • Mixed distribution of CAFs and cancer cells suppressed antitumor immunity more effectively than surrounding FB barriers.
  • This mixed distribution promoted immunosuppression via TGFβ and periostin cross-talk.
  • Postn knockdown in CAFs reduced TGFβ, enhanced antitumor immunity in vitro and in vivo.
  • Clinically, a mixed CAF-cancer cell distribution correlated with worse prognosis and lower CD8+ T-cell infiltration in patients undergoing PD-1 blockade therapy.

Conclusions:

  • Close spatial interactions between CAFs and cancer cells, not just physical barriers, are key drivers of immunosuppression.
  • Targeting CAF-cancer cell interactions and periostin presents a promising strategy for enhancing cancer immunotherapy.
  • 3D bioprinting offers a valuable platform for studying tumor microenvironment dynamics and spatial relationships.