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<p>Immune evasion by cancer cells involves reshaping the tumor microenvironment (TME) via communication with non-malignant cells. However, resistance-promoting interactions during treatment remain lesser known. Here we examine the composition, communication, and phenotypes of tumor-associated cells in serial biopsies from stage II and III high-risk estrogen receptor positive (ER+ ) breast cancers of patients receiving endocrine therapy (letrozole) as single agent or in combination with ribociclib, a CDK4/6-targeting cell cycle inhibitor. Single-cell RNA sequencing analyses on longitudinally collected samples show that in tumors overcoming the growth suppressive effects of ribociclib, first cancer cells upregulate cytokines and growth factors that stimulate immune-suppressive myeloid differentiation, resulting in reduced myeloid cell- CD8 + T-cell crosstalk via IL-15/18 signaling. Subsequently, tumors growing during treatment show diminished T-cell activation and recruitment. In vitro, ribociclib does not only inhibit cancer cell growth but also T cell proliferation and activation upon co-culturing. Exogenous IL-15 improves CDK4/6 inhibitor efficacy by augmenting T-cell proliferation and cancer cell killing by T cells. In summary, response to ribociclib in stage II and III high-risk ER +  breast cancer depends on the composition, activation phenotypes and communication network of immune cells.</p>

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Cellular interactions within the immune microenvironment underpins resistance to cell cycle inhibition in breast cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月3日

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  • Jason I. Griffiths,
  • Patrick A. Cosgrove,
  • Eric F. Medina,
  • Aritro Nath,
  • Jinfeng Chen,
  • Frederick R. Adler,
  • Jeffrey T. Chang,
  • Qamar J. Khan,
  • Andrea H. Bild

摘要

Immune evasion by cancer cells involves reshaping the tumor microenvironment (TME) via communication with non-malignant cells. However, resistance-promoting interactions during treatment remain lesser known. Here we examine the composition, communication, and phenotypes of tumor-associated cells in serial biopsies from stage II and III high-risk estrogen receptor positive (ER+ ) breast cancers of patients receiving endocrine therapy (letrozole) as single agent or in combination with ribociclib, a CDK4/6-targeting cell cycle inhibitor. Single-cell RNA sequencing analyses on longitudinally collected samples show that in tumors overcoming the growth suppressive effects of ribociclib, first cancer cells upregulate cytokines and growth factors that stimulate immune-suppressive myeloid differentiation, resulting in reduced myeloid cell- CD8 + T-cell crosstalk via IL-15/18 signaling. Subsequently, tumors growing during treatment show diminished T-cell activation and recruitment. In vitro, ribociclib does not only inhibit cancer cell growth but also T cell proliferation and activation upon co-culturing. Exogenous IL-15 improves CDK4/6 inhibitor efficacy by augmenting T-cell proliferation and cancer cell killing by T cells. In summary, response to ribociclib in stage II and III high-risk ER +  breast cancer depends on the composition, activation phenotypes and communication network of immune cells.