Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer

Abstract

Metastatic breast cancers (mBCs) are largely resistant to immune checkpoint blockade, but the mechanisms remain unclear. Primary breast cancers are characterized by a dense fibrotic stroma, which is considered immunosuppressive in multiple malignancies, but the stromal composition of breast cancer metastases and its role in immunosuppression are largely unknown. Here we show that liver and lung metastases of human breast cancers tend to be highly fibrotic, and unlike primary breast tumors, they exclude cytotoxic T lymphocytes (CTLs). Unbiased analysis of the The Cancer Genome Atlas database of human breast tumors revealed a set of genes that are associated with stromal T-lymphocyte exclusion. Among these, we focused onCXCL12as a relevant target based on its known roles in immunosuppression in other cancer types. We found that the CXCL12 receptor CXCR4 is highly expressed in both human primary tumors and metastases. To gain insight into the role of the CXCL12/CXCR4 axis, we inhibited CXCR4 signaling pharmacologically and found that plerixafor decreases fibrosis, alleviates solid stress, decompresses blood vessels, increases CTL infiltration, and decreases immunosuppression in murine mBC models. By deletingCXCR4in αSMA+cells, we confirmed that these immunosuppressive effects are dependent on CXCR4 signaling in αSMA+cells, which include cancer-associated fibroblasts as well as other cells such as pericytes. Accordingly, CXCR4 inhibition more than doubles the response to immune checkpoint blockers in mice bearing mBCs. These findings demonstrate that CXCL12/CXCR4-mediated desmoplasia in mBC promotes immunosuppression and is a potential target for overcoming therapeutic resistance to immune checkpoint blockade in mBC patients.

Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

“…Despite the success of targeting the stromal compartment in tumors (7,11,15,19,20,41), in particular tumor ECM, there are still a series of challenges that remained to be addressed. In the first part of this study we tackle two of these challenges.…”

“…In cholangiocarcinoma, an immune mesenchymal subtype has been identified, which is associated with TGF signature and poor tumor infiltrating cells (18). Other axes including the CXCR4/CXCL12 in breast metastasis and the focal adhesion kinase in pancreatic ductal adenocarcinoma (PDAC) have also been associated with both desmoplasia and absence of cytotoxic T lymphocytes in tumors from mice (19). Consequently, the inhibition of these axes in preclinical mouse cancer models was shown to reduce fibrosis while significantly increasing T cell infiltration and improving response to checkpoint inhibitors (7,16,20,21).…”

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…Vessel compression is a result of mechanical forces accumulated within stroma components of tumors (21)(22)(23). Indeed, our previous studies (24)(25)(26) showed that inhibiting CXCL12/CXCR4 or angiotensin signaling can target cancer-associated fibroblasts (CAFs) and extracellular collagen and hyaluronan, which in turn alleviates intratumoral forces, decompresses tumor vessels, and improves perfusion as well as the outcome of ICBs. We have referred to this approach as stroma normalization (27)(28)(29)(30).…”

“…Stroma and vascular normalization improve tumor perfusion and oxygenation and can enhance immune response by skewing TAM polarization toward the M1 phenotype, which is tumoricidal and immunostimulatory (10,13,24,39,40). This can also result in the activation of dendritic cells, cytotoxic T lymphocytes, and natural killer (NK) cells (39).…”

Chronic circadian disruption modulates breast cancer cell stemness and their immune microenvironment to drive metastasis in mice

“…Recent studies also suggest the use of CXCR2 or CXCR4 inhibitors in combination with immunotherapy to overcome therapeutic resistance. 82,88 These novel therapeutic strategies, together with the use of the new predictive tools based on clock genes expression for cancer prognosis will lead to a precision circadian medicine with improved efficacy and immunotherapy responsiveness. 39,89 In conclusion, our study provides for the first time experimental evidence of the link between CRD and an increase in cancer cell dissemination and metastasis formation.…”