TY - JOUR
T1 - PlexinB1 inactivation reprograms immune cells in the tumor microenvironment, inhibiting breast cancer growth and metastatic dissemination
AU - Franzolin, Giulia
AU - Brundu, Serena
AU - Cojocaru, Carina F.
AU - Curatolo, Aurora
AU - Ponzo, Matteo
AU - Mastrantonio, Roberta
AU - Mihara, Emiko
AU - Kumanogoh, Atsushi
AU - Suga, Hiroaki
AU - Takagi, Junichi
AU - Tamagnone, Luca
AU - Giraudo, Enrico
PY - 2024
Y1 - 2024
N2 - Semaphorin–Plexin signaling plays a major role in the tumor microenvironment (TME). In
particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis;
however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the
TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triplenegative murine breast carcinoma to elucidate its relevance in cancer progression. We found that
primary tumor growth, and metastatic dissemination were strongly reduced in PLXNB1-deficient
mice, which showed longer survival. PLXNB1-loss in the TME induced a switch in the polarization
of tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype and
enhanced the infiltration of CD8+
T lymphocytes both in primary tumors and in distant metastases.
Moreover, PLXNB1-deficiency promoted a shift in the Th1/Th2 balance of the T-cell population
and an antitumor gene signature, with the up-regulation of Icos, Perforin-1, Stat3 and Ccl5 in tumor
infiltrating lymphocytes (TILs). We thus tested the translational relevance of TME re-programming
driven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of
PLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor
growth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by
systemic treatment with a specific inhibitor significantly hampered breast cancer growth and
enhanced the antitumor activity of the anti-PD1 treatment in a preclinical model. Altogether, these
data indicate that PLXNB1 signaling controls the antitumor immune response in the TME and
highlight this receptor as a promising immune therapeutic target for metastatic breast cancers.
AB - Semaphorin–Plexin signaling plays a major role in the tumor microenvironment (TME). In
particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis;
however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the
TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triplenegative murine breast carcinoma to elucidate its relevance in cancer progression. We found that
primary tumor growth, and metastatic dissemination were strongly reduced in PLXNB1-deficient
mice, which showed longer survival. PLXNB1-loss in the TME induced a switch in the polarization
of tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype and
enhanced the infiltration of CD8+
T lymphocytes both in primary tumors and in distant metastases.
Moreover, PLXNB1-deficiency promoted a shift in the Th1/Th2 balance of the T-cell population
and an antitumor gene signature, with the up-regulation of Icos, Perforin-1, Stat3 and Ccl5 in tumor
infiltrating lymphocytes (TILs). We thus tested the translational relevance of TME re-programming
driven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of
PLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor
growth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by
systemic treatment with a specific inhibitor significantly hampered breast cancer growth and
enhanced the antitumor activity of the anti-PD1 treatment in a preclinical model. Altogether, these
data indicate that PLXNB1 signaling controls the antitumor immune response in the TME and
highlight this receptor as a promising immune therapeutic target for metastatic breast cancers.
KW - Immune cells, immunotherapy, breast cancer, metastasis
KW - Plexins
KW - Immune cells, immunotherapy, breast cancer, metastasis
KW - Plexins
UR - http://hdl.handle.net/10807/281476
U2 - 10.1158/2326-6066.CIR-23-0289
DO - 10.1158/2326-6066.CIR-23-0289
M3 - Article
SN - 2326-6066
VL - 12
SP - 1286
EP - 1301
JO - Cancer immunology research
JF - Cancer immunology research
ER -