Diverse immune suppressing cancer communications with myeloid cells prevent T cell activation and recruitment and provide resistance to cell cycle inhibitor therapy

ABSTRACT: Cancer cells evolve and acquire the ability to develop resistance to therapy and change their environment. A key mechanism involves altering communication with non-malignant cells in the tumor microenvironment (TME). By corrupting the signals for growth and survival, evolving tumors engineer a pro-tumor TME which contributes to the development of 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 examined the composition, communication, and phenotypic diversity of tumor-associated cell populations in serial biopsies from the FELINE clinical trial. Early-stage ER+ breast cancers receiving endocrine therapy (letrozole) alone or in combination with the CDK4/6 cell cycle inhibitor ribociclib 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 reduced T-cell activation and recruitment. Given cell cycle inhibitors known inhibitory effect on immune cell activation, in addition to also blocking cancer cell proliferation, maintenance of immune stimulatory cellular populations and signals that promote T-cell abundance and cytotoxicity is critical for treatment response. Our results show how altered communication promotes an immune-cold TME that predisposes tumors to develop CDK4/6 inhibitor resistance. A successful treatment strategy will require both the prevention of cancer division and also activation of a cytotoxic T-cell response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211434 | GEO | 2024/12/11

REPOSITORIES: GEO