Kindlin-2-Mediated Hematopoiesis Remodeling Regulates Triple-Negative Breast Cancer Immune Evasion

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.