Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

Griffiths, J. I.; Cosgrove, P. A.; Medina Castaneda, E.; Nath, A.; Chen, J.; Adler, F. R.; Chang, J. T.; Khan, Q. J.; Bild, A. H.

doi:10.1101/2022.09.14.507931

bioRxiv · 10.1101/2022.09.14.507931

Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance

Griffiths, J. I.·Cosgrove, P. A.·Medina Castaneda, E.·Nath, A.·Chen, J.·Adler, F. R.·Chang, J. T.·Khan, Q. J.·Bild, A. H.

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Abstract

Cancer cells evolve, acquire resistance to therapy and change their environment. One resistance mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving cancer cells can engineer a pro-tumor TME. 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. These patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor ribociclib, and were analyzed using single-cell RNA sequencing (scRNAseq). Our analyses reveal cancer cells from ribociclib resistant tumors stimulate macrophage differentiation towards an immune-suppressive phenotype through upregulation of a broad diversity of cytokines and growth factors. This shift in phenotype leads to reduced macrophage cell IL-15/-18 crosstalk with CD8+ T-cell via IL-2/15RA/18R receptors, resulting in diminished T-cell activation and recruitment. Thus, cancer communication promoting an immune-cold TME predispose tumors to develop CDK4/6 inhibitor resistance, and that the beneficial effects of cell cycle inhibitors through blocking cancer cell proliferation must be balanced against their known 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.

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Griffiths, J. I., Cosgrove, P. A., Medina Castaneda, E., Nath, A., Chen, J., Adler, F. R., Chang, J. T., Khan, Q. J., Bild, A. H.. 2022-09-17. Cancer cells communicate with macrophages to prevent T cell activation during development of cell cycle therapy resistance. https://doi.org/10.1101/2022.09.14.507931

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