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Introduction: Although most PD-L1-positive patients with metastatic triple-negative breast cancer (mTNBC) respond to immune check point inhibitors (ICIs) many either do not respond or develop resistance. Mechanisms of ICI resistance include low PD-L1 and T cell exhaustion. Preclinical studies show that CCR5 inhibition can both prevent tumor growth and reduce the size of established mTNBC. The current studies were conducted to identify molecular mechanisms by which the CCR5 inhibitor leronlimab may influence ICI responses in mTNBC. Methods: Patient gene-expression datasets, tissue-culture models, and clinical materials, including tumor histology and analyses of cancer-associated macrophages and circulating tumor cells were evaluated. Patients with mTNBC treated with leronlimab were analyzed to investigate CCR5-related mechanisms influencing ICI response. Findings: (1) Across four TNBC patient datasets, CCR5 gene expression positively correlated with cytotoxic T lymphocyte (CTL) levels. In a breast cancer cohort (N=1,094) CCR5 expression strongly correlated with T cell exhaustion signatures. An ImmunoPhenotype score identifying CCR5High immune states was highly associated with CCR5 expression in TNBC; (2) CCR5 expression on human TNBC cell lines suppressed the abundance of glycosylated PD‑L1. CCR5 inhibition, with leronlimab increased the abundance of PD‑L1 (18 and 55 kDa); (3) In cultured TNBC breast cancer cells, a CCR5 mediated secretome was identified. CCR5 activity induced sB7H3 (CD276) (known to promote T cell exhaustion), sTNFSF13B (BAFF), sTyro3 (linked to breast cancer ferroptosis inhibition) and Tyro3 ligand. CCR5 inhibition with leronlimab reduced sB7H3, sTNFSF13B and sTyro3; (4) Rhesus macaques that received a single 50 mg/kg dose of leronlimab showed reduced T cell exhaustion markers on lymph-node-resident CD4+ and CD8+ T cells. At one week, when leronlimab levels were highest, CD8+ T cells showed a marked decline in LAG3, TIM3 and CTLA4 expression. Leronlimab-mediated CCR5 blockade reduced these key exhaustion markers followed by a later rise in PD-1 expression at four weeks, a pattern consistent with reactivated T-cell signaling rather than terminal exhaustion. CCR5 receptor binding on CD8+ T cells coincided with this significant increase in PD-1 expression; (5) In a pooled retrospective analysis of 28 heavily pretreated mTNBC patients from three clinical trials, leronlimab was well tolerated with no therapy-limiting toxicities. Remarkably after a median of >60 months 5/28 (17.9%) of patients remain alive. Conclusions: CCR5 may contribute to ICI resistance in TNBC by promoting T-cell exhaustion and driving immunosuppressive checkpoint pathways (including sB7-H3 and sTyro3). Leronlimab blocks CCR5 signaling, reduces exhaustion markers, suppresses multiple immunosuppressive mediators, and increases PD-L1 expression on tumor-associated cells; changes that may sensitize tumors to PD-1/PD-L1 blockade. Together, these findings support a mechanistic rationale for combining leronlimab with ICIs to enhance therapeutic responses in mTNBC.
Introduction: Although most PD-L1-positive patients with metastatic triple-negative breast cancer (mTNBC) respond to immune check point inhibitors (ICIs) many either do not respond or develop resistance. Mechanisms of ICI resistance include low PD-L1 and T cell exhaustion. Preclinical studies show that CCR5 inhibition can both prevent tumor growth and reduce the size of established mTNBC. The current studies were conducted to identify molecular mechanisms by which the CCR5 inhibitor leronlimab may influence ICI responses in mTNBC. Methods: Patient gene-expression datasets, tissue-culture models, and clinical materials, including tumor histology and analyses of cancer-associated macrophages and circulating tumor cells were evaluated. Patients with mTNBC treated with leronlimab were analyzed to investigate CCR5-related mechanisms influencing ICI response. Findings: (1) Across four TNBC patient datasets, CCR5 gene expression positively correlated with cytotoxic T lymphocyte (CTL) levels. In a breast cancer cohort (N=1,094) CCR5 expression strongly correlated with T cell exhaustion signatures. An ImmunoPhenotype score identifying CCR5High immune states was highly associated with CCR5 expression in TNBC; (2) CCR5 expression on human TNBC cell lines suppressed the abundance of glycosylated PD‑L1. CCR5 inhibition, with leronlimab increased the abundance of PD‑L1 (18 and 55 kDa); (3) In cultured TNBC breast cancer cells, a CCR5 mediated secretome was identified. CCR5 activity induced sB7H3 (CD276) (known to promote T cell exhaustion), sTNFSF13B (BAFF), sTyro3 (linked to breast cancer ferroptosis inhibition) and Tyro3 ligand. CCR5 inhibition with leronlimab reduced sB7H3, sTNFSF13B and sTyro3; (4) Rhesus macaques that received a single 50 mg/kg dose of leronlimab showed reduced T cell exhaustion markers on lymph-node-resident CD4+ and CD8+ T cells. At one week, when leronlimab levels were highest, CD8+ T cells showed a marked decline in LAG3, TIM3 and CTLA4 expression. Leronlimab-mediated CCR5 blockade reduced these key exhaustion markers followed by a later rise in PD-1 expression at four weeks, a pattern consistent with reactivated T-cell signaling rather than terminal exhaustion. CCR5 receptor binding on CD8+ T cells coincided with this significant increase in PD-1 expression; (5) In a pooled retrospective analysis of 28 heavily pretreated mTNBC patients from three clinical trials, leronlimab was well tolerated with no therapy-limiting toxicities. Remarkably after a median of >60 months 5/28 (17.9%) of patients remain alive. Conclusions: CCR5 may contribute to ICI resistance in TNBC by promoting T-cell exhaustion and driving immunosuppressive checkpoint pathways (including sB7-H3 and sTyro3). Leronlimab blocks CCR5 signaling, reduces exhaustion markers, suppresses multiple immunosuppressive mediators, and increases PD-L1 expression on tumor-associated cells; changes that may sensitize tumors to PD-1/PD-L1 blockade. Together, these findings support a mechanistic rationale for combining leronlimab with ICIs to enhance therapeutic responses in mTNBC.
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