Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

Albini, Adriana; Bruno, Antonino; Noonan, Douglas M.; Mortara, Lorenzo

doi:10.3389/fimmu.2018.00527

Cited by 323 publications

(342 citation statements)

References 261 publications

(290 reference statements)

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“…The cells are capable of recognizing and killing cancer cells without a requirement for antigen exposure (Baek et al, 2018). NK cells have antitumor ability in an immature state, while differentiated NK cells acquire PD-1 receptor that is expressed at a considerable rate upon tumor progression (Albini, Bruno, Noonan, & Mortara, 2018). There are two phenotypes for NK cells: canonical and adoptive.…”

Section: Nk Cellsmentioning

confidence: 99%

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Contribution of regulatory T cells to cancer: A review

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

155

103

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Regulatory T cells (Tregs) represent a low number of T‐cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross‐talks with other immunosuppressive cells including cancer‐associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid‐derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor‐β, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor‐bearing receptors in Tregs, including FOXP3, programmed death‐1, T‐cell immunoglobulin mucin‐3, and CTL‐associated antigen‐4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg.

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Section: Nk Cellsmentioning

confidence: 99%

“…STAT3 also promotes cancer cell survival (Kesanakurti, Chetty, Dinh, Gujrati, & Rao, 2013). In addition, STAT3 is a stimulator of tumor angiogenesis (Albini et al, 2018). Signaling pathways directed by STAT has been clarified in Figure 3.…”

Section: Statmentioning

confidence: 99%

Contribution of regulatory T cells to cancer: A review

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

155

103

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“…Immunohistochemistry analysis showed a clear rebalance (i.e., an increment) of M1/M2 polarization ratio in C51 FL Rnaset2-injected mice, concomitant with inhibition of MDSCs, granulocytes and vessel numbers. The myeloid cell compartment appears to be a crucial determinant in the fate of tumor growth [27], indeed M2-like macrophages and/or TAMs as well as MDSCs associate with worse tumor clinical outcome, tumor dissemination, angiogenesis, immunosuppression, and metastasis [21,35,36]. Concerning tumor angiogenesis, it has been reported that several derivative peptides from human RNASET2 protein structure can exert antiangiogenic effects using HUVEC tube formation assay and using ex vivo CAM assay, and this effect is dependent on the peptide's ability to bind actin [37].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection

Vito

Orecchia

Balza

et al. 2020

Cancers

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Human RNASET2 acts as a powerful oncosuppressor protein in in vivo xenograft-based murine models of human cancer. Secretion of RNASET2 in the tumor microenvironment seems involved in tumor suppression, following recruitment of M1-polarized macrophages. Here, we report a murine Rnaset2-based syngeneic in vivo assay. BALB/c mice were injected with parental, empty vector-transfected or murine Rnaset2-overexpressing mouse C51 or TS/A syngeneic cells and tumor growth pattern and immune cells distribution in tumor mass were investigated. Compared to control cells, mouse Rnaset2-expressing C51 cells showed strong delayed tumor growth. CD86 + M1 macrophages were massively recruited in Rnaset2-expressing C51-derived tumors, with concomitant inhibition of MDSCs and CD206 + M2 macrophages recruitment. At later times, a relevant expansion of intra-tumor CD8 + T cells was also observed. After re-challenge with C51 parental cells, most mice previously injected with Rnaset2-expressing C51 cells still rejected C51 tumor cells, suggesting a Rnaset2-mediated T cell adaptive immune memory response. These results point at T2 RNases as evolutionary conserved oncosuppressors endowed with the ability to inhibit cancer growth in vivo through rebalance of intra-tumor M1/M2 macrophage ratio and concomitant recruitment of adaptive anti-tumor CD8 + T cells.Cancers 2020, 12, 717 2 of 18 in tumor suppression. Indeed, two independent in vivo xenograft-based murine models of human ovarian cancer have been previously used to demonstrate a marked RNASET2-mediated in vivo tumor suppression [1,2]. It has been previously shown that RNASET2 affects several important cancer-related parameters (such as modulation of cell proliferation, cytoskeletal re-organization, cell adhesion, motility, and angiogenesis) in a cell-autonomous manner, [3][4][5][6]. Moreover, further studies in both in vitro and in vivo experimental models have demonstrated a marked modulation of macrophage plasticity played by the RNASET2 protein, thus suggesting the occurrence of a RNASET2-mediated noncell-autonomous oncosuppressive role [7]. In fact, human RNASET2 overexpression in two independent human ovarian cancer cell lines, followed by challenging of immunodeficient mouse models with these cells, showed a marked tumor suppressive effect coupled with a RNASET2-mediated recruitment of M1-polarized host macrophages within the tumor mass [1,2]. These data, coupled to the well-established notion of T2 RNases as stress response genes [8,9], strongly suggest that human RNASET2 secretion by cancer cells might represent a "danger" signal for cells belonging to the monocyte/macrophage lineage, whose role would be to trigger an effective host immune response. Of note, the macrophage-activating role of T2 RNases has been recently confirmed in species far away from mammals in term of evolutionary distance, such as the invertebrate Hirudo verbana [10], thus pointing at T2 RNases as highly conserved immune system-related stress response proteins acting across many Phyla.The concept that the ...

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“…Additionally, the high expression of granzyme B and FasL in cytotoxic cells of the tumor microenvironment was obviously observed in the combination-treated mice (Figure 5d). [22] Compared to PLG-CA4 alone, the CD31-positive signals were further reduced, and the intertumor microvessels were poorly structured after treatment with PI3Kγ inhibitor (Figure 5e). The critical role of tumorinfiltrating macrophages in promoting tumor angiogenesis is strongly established.…”

Section: Mechanisms Of Antitumor Performance By Attenuating Immunosupmentioning

confidence: 97%

PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l‐Glutamic Acid)‐Combretastatin A4 Conjugate in Metastatic Breast Cancer

Qin

Sheng

et al. 2019

Advanced Science

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Vascular disrupting agents (VDAs) have great potential for cancer treatment. Poly( l ‐glutamic acid)‐combretastatin A4 conjugate (PLG‐CA4) is a novel class of VDAs. Though it has notable antitumor activity, it can induce host immune responses that promote tumor growth. Here, PLG‐CA4 induces the polarization of tumor‐associated macrophages (TAMs) toward the M2‐like phenotype in 4T1 metastatic breast cancer (Control 30% vs PLG‐CA4 53%; p < 0.05). Compared to the monotherapy of PLG‐CA4, inhibition of phosphoinositide 3‐kinase gamma (PI3Kγ) attenuates the immunosuppressive effect of PLG‐CA4 treatment by decreasing the number of M2‐like TAMs (2.0 × 10 4 to 1.5 × 10 4 per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 × 10 4 to 5.7 × 10 4 per tumor). Importantly, PI3Kγ inhibitor synergizing with PLG‐CA4 significantly extends the mean survival time from 52 days in monotherapy‐treated mice to 61.8 days. Additionally, the combination of PLG‐CA4 and PI3Kγ inhibitor improves the tumor therapeutic effect of NLG919, an inhibitor of immune checkpoint indoleamine 2,3‐dioxygenase (IDO). As far as it is known, this is the first demonstrated study that VDAs induce the reshaping of macrophages to the M2‐like phenotype. The findings also indicate a potential therapeutic strategy of the combination VDAs with an accurate immune modifier in the tumor to reverse the immune resistance.

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Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

Cited by 323 publications

References 261 publications

Contribution of regulatory T cells to cancer: A review

Contribution of regulatory T cells to cancer: A review

Overexpression of Murine Rnaset2 in a Colon Syngeneic Mouse Carcinoma Model Leads to Rebalance of Intra-Tumor M1/M2 Macrophage Ratio, Activation of T Cells, Delayed Tumor Growth, and Rejection

PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l‐Glutamic Acid)‐Combretastatin A4 Conjugate in Metastatic Breast Cancer

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