Triple-negative breast cancer (TNBC) presents significant clinical challenges because of its limited treatment options and aggressive behavior, often associated with poor prognosis. This study focuses on kindlin-2, an adapter protein, and its role in TNBC progression, particularly in hematopoiesis-mediated immune evasion. TNBC tumors expressing high levels of kindlin-2 induce a notable reshaping of hematopoiesis, promoting the expansion of myeloid cells in the bone marrow and spleen. This shift correlated with increased levels of neutrophils and monocytes in tumor-bearing mice over time. Conversely, genetic knockout (KO) of kindlin-2 mitigated this myeloid bias and fostered T-cell infiltration within the tumor microenvironment, indicating the pivotal role of kindlin-2 in immune modulation. Further investigations revealed that kindlin-2 deficiency led to reduced expression of PD-L1, a critical immune checkpoint inhibitor, in TNBC tumors. This molecular change sensitized kindlin-2–deficient tumors to host antitumor immune responses, resulting in enhanced tumor suppression in immunocompetent mouse models. Single-cell RNA sequencing, bulk RNA sequencing, and IHC data supported these findings by highlighting enriched immune-related pathways and increased infiltration of immune cells in kindlin-2–deficient tumors. Therapeutically, targeting PD-L1 in kindlin-2–expressing TNBC tumors effectively inhibited tumor growth, akin to the effects observed with genetic kindlin-2 KO or PD-L1 KO. Our data underscore kindlin-2 as a promising therapeutic target in combination with immune checkpoint blockade to bolster antitumor immunity and counteract resistance mechanisms typical of TNBC and other immune-evasive solid tumors.

Implications: Kindlin-2 regulates tumor immune evasion through the systemic modulation of hematopoiesis and PD-L1 expression, which warrants therapeutic targeting of kindlin-2 in patients with TNBC.

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©2025 American Association for Cancer Research
2025
American Association for Cancer Research

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Supplementary data

Supplementary Table S1

Supplementary Table S1. Sequence of sgRNAs used for CRISPR/Cas9-mediated knockout of the genes involved in this study

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Supplementary Table S2

Supplementary Table S2. Mouse antibodies panel for Akoya STEP multiplex immunostaining.

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Supplementary Figure S1

Supplementary Figure S1. Immunophenotypic analysis of myeloid, B and T cells from bone marrow and splenic preps of naïve, or 4T1 injected mice, two- and five-weeks following cell infusion.

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Supplementary Figure S2

Supplementary Figure S2. K2 KO alters hematopoietic dynamics during D2A1 tumor progression.

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Supplementary Figure S3

Supplementary Figure S3. Immunophenotypic analysis of myeloid, B and T cells from bone marrow and splenic preps of Control or K2 KO 4T1 injected mice, two- and five-weeks following cell infusion.

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Supplementary Figure S4

Supplementary Figure S4. Pathway analyses of the scRNA-seq data using Gene Ontology biological functions analyses.

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Supplementary Figure S5

Supplementary Figure S5. Heat map plot from the bulk RNA-seq analyses of the DEGs between the parental and Kindlin-2-KO 4T1 cells.

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Supplementary Figure S6

Supplementary Figure S6. mRNA co-expression of Kindlin-2 (FERMT2) and PD-L1 (CD274) in breast cancer tumors (n = 1,082 patients).

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Supplementary Figure S7

Supplementary Figure S7. Comparison of mRNA expression levels of PD-L1 (CD274) between the different breast Cancer molecular subtypes.

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Supplementary Figure S8

Supplementary Figure S8. Gene Set Enrichment Analysis (GSEA) of RNA-seq data shows that Kindlin-2 expression levels correlate with gene signatures involved in Chemokine Signaling.

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Supplementary Figures Legends

Legends for Supplementary Figures

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