Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Abstract

Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells.

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

“…Similar findings were obtained with BT cells, where we compared cells that expressed endogenous PD-L1 at relatively low levels and were infected by a control vector (“CTRL Vector” cells), and their counterparts that were infected to over-express WT PD-L1 (“WT PD-L1” cells) ( Figure S6B shows PD-L1 expression in different cells from those used in our published study [ 66 ]; the current ones do not express mCherry). The data of Figure 11 (B1,B2) demonstrate that although BT cells that expressed WT PD-L1 had a higher proliferation rate than CTRL Vector cells, the former produced lower levels of sTNFR1 and sTNFR2 than the latter.…”

“…Together, these findings illustrate a regulatory mechanism which is mediated by PD-L1, reducing the expression of sTNFR1 and sTNFR2 that have protective anti-malignancy roles. In view of our published findings indicating that higher expression levels of PD-L1 in TNBC cells lead to increased extracellular levels of the pro-metastatic chemokines CXCL8, CXCL1 and CCL5 [ 66 ], our current observations propose that by inhibiting sTNFR1 and sTNFR2 expression, PD-L1 contributes to increased production of the pro-metastatic chemokines, and thus to the pro-malignancy potential of the cancer cells.…”

“…In parallel, BT cells that expressed endogenous PD-L1 were infected to over-express WT PD-L1 or infected by an empty vector control. These BT cells differed from those used in our published study [ 66 ] by the fact that they did not express mCherry.…”

“…When indicated, the study included MDA cells and BT cells that were manipulated to over-express PD-L1, as described in [ 66 ]. Briefly, in MDA cells we have compared between cells that expressed PD-L1 and cells that did not express PD-L1 at any level.…”

Correction: Erlichman et al. Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes. Cancers 2022, 14, 1042

“…The authors apologize for several typos/technical inaccuracies in the original article [ 1 ]: References 36 and 38 have mistakenly addressed sPD-L1, instead of sPD-1; relevant references on sPD-1 are: PMIDs 33499013, and 26859684 (Pubmed). In page 19, line 33 from the top, the correct reference is 33.…”