WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer

Lorenzo Castagnoli, Valeria Cancila, Sandra L. Cordoba-Romero, Simona Faraci, Giovanna Talarico, Beatrice Belmonte, Marilena V. Iorio, Matteo Milani, Tatiana Volpari, Claudia Chiodoni, Alfredo Hidalgo-Miranda, Elda Tagliabue, Claudio Tripodo, Sabina Sangaletti, Massimo Di Nicola, Serenella M. Pupa

Research output: Contribution to journalArticlepeer-review

Abstract

Triple-negative breast cancers (TNBCs) are characterized by a poor prognosis and lack of targeted treatments, and thus, new therapeutic strategies are urgently needed. Inhibitors against programmed death-1 (PD-1)/PD-1 ligand (PD-L1) have shown significant efficacy in various solid cancers, but their activity against TNBCs remains limited. Here, we report that human TNBCs molecularly stratified for high levels of PD-L1 (PD-L1High) showed significantly enriched expression of immune and cancer stemness pathways compared with those with low PD-L1 expression (PD-L1Low). In addition, the PD-L1High cases were significantly associated with a high stemness score (SSHigh) signature. TNBC cell lines gated for aldehyde dehydrogenase (ALDH) and CD44 stemness markers exhibited increased levels of PD-L1 versus their ALDH-negative and CD44Low counterparts, and PD-L1High cells generated significantly more mammospheres than PD-L1Low cells. Murine mammary SCA-1-positive tumor cells with PD-L1High expression generated tumors in vivo with higher efficacy than PD-L1Low cells. Furthermore, treatment of TNBC cells with selective WNT inhibitors or activators downregulated or upregulated PD-L1 expression, respectively, implying a functional cross-talk between WNT activity and PD-L1 expression. Remarkably, human TNBC samples contained tumor elements co-expressing PD-L1 with ALDH1A1 and/or CD44v6. Additionally, both PD-L1-/SCA1-positive and ALDH1A1-positive tumor elements were found in close contact with CD3-, and PD-1-positive T cells in murine and human tumor samples. Overall, our study suggests that PD-L1-positive tumor elements with a stemness phenotype may participate in the complex dynamics of TNBC-related immune evasion, which might be targeted through WNT signaling inhibition.

Original languageEnglish
Pages (from-to)4047-4060
Number of pages14
JournalOncogene
Volume38
Issue number21
DOIs
Publication statusPublished - May 23 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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