Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer

Santagata, Sara; Napolitano, Maria; D’Alterio, Crescenzo; Desicato, Sonia; Maro, Salvatore Di; Marinelli, Luciana; Fragale, Alessandra; Buoncervello, Maria; Persico, Francesco; Gabriele, Lucia; Novellino, Ettore; Longo, Nicola; Pignata, Sandro; Perdonà, Sisto; Scala, Stefania

doi:10.18632/oncotarget.20363

Cited by 60 publications

(39 citation statements)

References 32 publications

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“…In our current study, we demonstrated that AMD3100 promoted the conversion of phenotypically suppressive CD25 þ Foxp3 þ T reg cells to CD25 -Foxp3 þ IL2 þ CD40L þ helper-like cells (33), which may result in the loss of immunosuppressive function of intratumoral T regs (34,35). In a similar scenario, a study on renal cell carcinoma demonstrates that CXCR4 antagonism elicited by a new peptidic antagonist, Peptide-R29, reverted the suppressive activity of T regs (50). Meiron and colleagues demonstrate, in opposition, that CXCL12 redirected the polarization of Th1 cells into IL10producing T regs (55).…”

Section: Discussionsupporting

confidence: 54%

“…However, we also found that PD-1 expression was significantly upregulated on tumor-infiltrating T cells in VIC-008-treated mice and that this was associated with high CXCL12 expression in the intratumoral microenvironment. These data indicated that the CXCL12-CXCR4 axis in the intratumoral microenvironment, itself, may modulate the PD-1/PD-L1 pathway and that the antitumor activity of tumor-infiltrating T cells could be compromised by PD-1/PD-L1 pathway activation (50). This is consistent with previous findings that CXCR4 inhibition or blockade of CXCL12 in the tumor microenvironment facilitates PD-1 blockade immunotherapy in hepatocellular carcinoma (22), pancreatic cancer (31), and colorectal cancer (32).…”

Section: Discussionmentioning

confidence: 90%

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AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression

Zeng

Reeves

et al. 2018

Cancer Immunology Research

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AMD3100 (plerixafor), a CXCR4 antagonist, has been demonstrated to suppress tumor growth and modulate intratumoral T-cell trafficking. However, the effect of AMD3100 on immunomodulation remains elusive. Here, we explored immunomodulation and antitumor efficacy of AMD3100 in combination with a previously developed mesothelin-targeted, immune-activating fusion protein, VIC-008, in two syngeneic, orthotopic models of malignant mesothelioma in immunocompetent mice. We showed that combination therapy significantly suppressed tumor growth and prolonged animal survival in two mouse models. Tumor control and survival benefit were associated with enhanced antitumor immunity. VIC-008 augmented mesothelin-specific CD8 T-cell responses in the spleen and lymph nodes and facilitated intratumoral lymphocytic infiltration. However, VIC-008 treatment was associated with increased programmed cell death protein-1 (PD-1) expression on intratumoral CD8 T cells, likely due to high CXCL12 in the tumor microenvironment. AMD3100 alone and in combination with VIC-008 modulated immunosuppression in tumors and the immune system through suppression of PD-1 expression on CD8 T cells and conversion of regulatory T cells (T) into CD4CD25Foxp3IL2CD40L helper-like cells. In mechanistic studies, we demonstrated that AMD3100-driven T reprogramming required T cell receptor (TCR) activation and was associated with loss of PTEN due to oxidative inactivation. The combination of VIC-008 augmentation of tumor-specific CD8 T-cell responses with AMD3100 abrogation of immunosuppression conferred significant benefits for tumor control and animal survival. These data provide new mechanistic insight into AMD3100-mediated immunomodulation and highlight the enhanced antitumor effect of AMD3100 in combination with a tumor antigen-targeted therapy in mouse malignant mesothelioma, which could be clinically relevant to patients with this difficult-to-treat disease. .

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 90%

AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression

Zeng

Reeves

et al. 2018

Cancer Immunology Research

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“…Moreover, CXCR4 is highly expressed also by the subset of immunosuppressive Treg cells. CXCR4 and its inhibition have been demonstrated in different tumor types to efficiently revert Treg suppression of T effectors proliferation, improving anticancer immune responses ( 23 , 67 ).…”

Section: Discussionmentioning

confidence: 99%

CXCR4 Inhibition Counteracts Immunosuppressive Properties of Metastatic NSCLC Stem Cells

et al. 2020

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Cancer stem cells (CSCs) are functionally defined as the cell subset with greater potential to initiate and propagate tumors. Within the heterogeneous population of lung CSCs, we previously identified highly disseminating CD133+CXCR4+ cells able to initiate distant metastasis (metastasis initiating cells-MICs) and to resist conventional chemotherapy. The establishment of an immunosuppressive microenvironment by tumor cells is crucial to sustain and foster metastasis formation, and CSCs deeply interfere with immune responses against tumors. How lung MICs can elude and educate immune cells surveillance to efficiently complete the metastasis cascade is, however, currently unknown. We show here in primary tumors from non-small cell lung cancer (NSCLC) patients that MICs express higher levels of immunoregulatory molecules compared to tumor bulk, namely PD-L1 and CD73, an ectoenzyme that catalyzes the production of immunosuppressive adenosine, suggesting an enhanced ability of MICs to escape immune responses. To investigate in vitro the immunosuppressive ability of MICs, we derived lung spheroids from cultures of adherent lung cancer cell lines, showing enrichment in CD133+CXCR4+MICs, and increased expression of CD73 and CD38, an enzyme that also concurs in adenosine production. MICs-enriched spheroids release high levels of adenosine and express the immunosuppressive cytokine IL-10, undetectable in an adherent cell counterpart. To prevent dissemination of MICs, we tested peptide R, a novel CXCR4 inhibitor that effectively controls in vitro lung tumor cell migration/invasion. Notably, we observed a decreased expression of CD73, CD38, and IL-10 following CXCR4 inhibition. We also functionally proved that conditioned medium from MICs-enriched spheroids compared to adherent cells has an enhanced ability to suppress CD8+ T cell activity, increase Treg population, and induce the polarization of tumor-associated macrophages (TAMs), which participate in suppression of T cells. Treatment of spheroids with anti-CXCR4 rescued T cell cytotoxic activity and prevented TAM polarization, likely by causing the decrease of adenosine and IL-10 production. Overall, we provide evidence that the subset of lung MICs shows high potential to escape immune control and that inhibition of CXCR4 can impair both MICs dissemination and their immunosuppressive activity, therefore potentially providing a novel therapeutic target in combination therapies to improve efficacy of NSCLC treatment.

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“…This involve regulatory T cells (Tregs), that secrete immunosuppressive cytokines, leading to T cell dysfunction . Previous study has shown Tregs can efficiently suppress effector T cells proliferation in RCC . Tumor‐associated macrophages (TAM) are another very important immune population that can either promote or block tumor development .…”

Section: Introductionmentioning

confidence: 99%

Immune infiltration in renal cell carcinoma

et al. 2019

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Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma ( RCC ). Tumor‐infiltrating immune cells ( TIIC s) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIIC s in RCC and further reveal the independent prognostic values of TIIC s. CIBERSORT , an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIIC s and immune checkpoint modulators with overall survival ( OS ). We found that CD 8+ T cells were associated with prolonged OS (hazard ratio [ HR ] = 0.09, 95% confidence interval [ CI ].01‐.53; P = 0.03) in chromophobe carcinoma ( KICH ). A higher proportion of regulatory T cells was associated with a worse outcome ( HR = 1.59, 95% CI 1.23‐.06; P < 0.01) in renal clear cell carcinoma ( KIRC ). In renal papillary cell carcinoma ( KIRP ), M1 macrophages were associated with a favorable outcome ( HR = .43, 95% CI .25‐.72; P < 0.01), while M2 macrophages indicated a worse outcome ( HR = 2.55, 95% CI 1.45‐4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA 4 and LAG 3 were associated with a poor prognosis in KIRC , and IDO 1 and PD ‐L2 were associated with a poor prognosis in KIRP . This study indicates TIIC s are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.

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Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer

Cited by 60 publications

References 32 publications

AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression

AMD3100 Augments the Efficacy of Mesothelin-Targeted, Immune-Activating VIC-008 in Mesothelioma by Modulating Intratumoral Immunosuppression

CXCR4 Inhibition Counteracts Immunosuppressive Properties of Metastatic NSCLC Stem Cells

Immune infiltration in renal cell carcinoma

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