Abstract 4318: Cancer cell communication with macrophages prevents T cell activation during emergence of cell cycle therapy resistance

Abstract By corrupting signals for growth and survival, evolving cancer cells can engineer the tumor microenvironment (TME) to promote treatment resistance. However, the specific interactions between malignant and non-malignant cells that predispose drug resistance and their changes during treatment remain widely unknown. Here we examine the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from early-stage ER+ breast cancers. We used single-cell RNA sequencing to profile over 400 thousand malignant and non-malignant cells from patient tumor samples obtained before, during and after treatment. The patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor (ribociclib). Our analyses reveal that cancer cells from ribociclib-resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a diversity of cytokines and growth factors. The macrophage phenotype shift leads to reduced crosstalk with cytotoxic T-cells via IL-2/15/18 receptors, diminishing T-cell activation and recruitment. These results indicate that cancer communications promoting an immune-cold TME predispose tumors to develop CDK4/6 cell cycle inhibitor resistance, and that the beneficial effects of blocking cancer cell proliferation must be balanced against their inhibitory effect on immune cell division and activation. An optimal treatment strategy will require coupling the prevention of cancer division with activation of an effective cytotoxic T-cell response. Citation Format: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild. Cancer cell communication with macrophages prevents T cell activation during emergence of cell cycle therapy resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4318.