Semaphorin and Plexin signaling, initially characterized for its role in axonal navigation, has been implicated in a number of diseases and plays a major role in the tumor context as well. Semaphorin4D (SEMA4D), in particular, has been shown to affect tumor growth and the tumor microenvironment (TME). However, at present the role of the SEMA4D high-affinity receptor PlexinB1 (PLXNB1) in the TME has been poorly characterized. The aim of this thesis project has been to study the role of PLXNB1 in the TME in the metastatic triple-negative murine breast carcinoma 4T1 model and its contribution to tumor progression. We found that primary tumor growth and metastatic dissemination were strongly reduced when 4T1 tumor cells were injectedorthotopically in PLXNB1 deficient mice. PLXNB1 deficiency in the TME did not affect tumor vessel density but enhanced vessel normalization by increasing pericyte coverage and reducing intra-tumoral hypoxia. Notably, in PLXNB1 deficient mice we observed an increased infiltration of CD8+ T lymphocytes, CD11c+antigen presenting cells and a reduction of myeloid derived suppressor cells. In addition, in Plxinb1 -/- mice as compared with WT animals, we detected a switch in the polarization status of tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype. Interestingly, treatment of Plxnb1 -/- mice with a CD8 blocking antibody enhanced cancer growth and metastasis number, indicating that CD8+T-cell recruitmentcontributes to the anti-tumor effect observed in Plxnb1-/- mice. In line with these observations, in tumors grown in Plxnb1-/- mice we detected enhanced expression of factors shown to mediate the activity of infiltrated lymphocytes, such as IFNγ and Chemokine (C-X-C motif) ligand 9 (CXCL9). On the basis of the strong impact of PLXNB1 deficiency in re-programming the TME, leading to a more suppressive tumor milieu, we tested its therapeutic use in combination with immunotherapy. Remarkably, we found that PLXNB1 deficiency strongly enhanced the efficacy of anti-PD-1 blocking antibody, efficiently reducing tumor growth and distal metastasis. Altogether, these data suggest that PLXNB1 is a promising therapeutic target for metastatic breast tumors and that its blockade can improve immunomodulatory therapies.
PlexinB1 deficiency in the microenvironment inhibits tumor growth and metastatic dissemination in a murine breast cancer model
Franzolin, Giulia
2021-01-01
Abstract
Semaphorin and Plexin signaling, initially characterized for its role in axonal navigation, has been implicated in a number of diseases and plays a major role in the tumor context as well. Semaphorin4D (SEMA4D), in particular, has been shown to affect tumor growth and the tumor microenvironment (TME). However, at present the role of the SEMA4D high-affinity receptor PlexinB1 (PLXNB1) in the TME has been poorly characterized. The aim of this thesis project has been to study the role of PLXNB1 in the TME in the metastatic triple-negative murine breast carcinoma 4T1 model and its contribution to tumor progression. We found that primary tumor growth and metastatic dissemination were strongly reduced when 4T1 tumor cells were injectedorthotopically in PLXNB1 deficient mice. PLXNB1 deficiency in the TME did not affect tumor vessel density but enhanced vessel normalization by increasing pericyte coverage and reducing intra-tumoral hypoxia. Notably, in PLXNB1 deficient mice we observed an increased infiltration of CD8+ T lymphocytes, CD11c+antigen presenting cells and a reduction of myeloid derived suppressor cells. In addition, in Plxinb1 -/- mice as compared with WT animals, we detected a switch in the polarization status of tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype. Interestingly, treatment of Plxnb1 -/- mice with a CD8 blocking antibody enhanced cancer growth and metastasis number, indicating that CD8+T-cell recruitmentcontributes to the anti-tumor effect observed in Plxnb1-/- mice. In line with these observations, in tumors grown in Plxnb1-/- mice we detected enhanced expression of factors shown to mediate the activity of infiltrated lymphocytes, such as IFNγ and Chemokine (C-X-C motif) ligand 9 (CXCL9). On the basis of the strong impact of PLXNB1 deficiency in re-programming the TME, leading to a more suppressive tumor milieu, we tested its therapeutic use in combination with immunotherapy. Remarkably, we found that PLXNB1 deficiency strongly enhanced the efficacy of anti-PD-1 blocking antibody, efficiently reducing tumor growth and distal metastasis. Altogether, these data suggest that PLXNB1 is a promising therapeutic target for metastatic breast tumors and that its blockade can improve immunomodulatory therapies.
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