Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Molon, Barbara; Ugel, Stefano; Pozzo, Federica Del; Soldani, Cristiana; Zilio, Serena; Avella, Debora; Palma, Antonella De; Mauri, Pierluigi; Monegal, Ana; Rescigno, María; Savino, Benedetta; Colombo, Piergiuseppe; Jonjić, Nives; Pečanić, Sanja; Lazzarato, Loretta; Fruttero, Roberta; Gasco, Alberto; Bronte, Vincenzo; Viola, Antonella

doi:10.1084/jem.20101956

Cited by 564 publications

(524 citation statements)

References 73 publications

(112 reference statements)

Supporting

Mentioning

512

Contrasting

Unclassified

Order By: Relevance

“…It is possible that posttranslational inactivating modifications of CCL2 may prevent effective CD8 + T cell recruitment in WT mice, thus permitting rapid tumor growth. This suggestion follows from an elegant study showing that intratumoral reactive nitrogen species induce CCL2 nitration that prevents CD8 + T cell infiltration (49). Notwithstanding, our study provides, to our knowledge, the first evidence for an antitumor role of CCL2 linked to gd T cell recruitment, representing an important addition to the pleiotropic functions of CCL2 in the tumor microenvironment.…”

Section: Discussionsupporting

confidence: 61%

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

Lança

Costa

Gonçalves-Sousa

et al. 2013

The Journal of Immunology

152

130

View full text Add to dashboard Cite

Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although γδ T lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by our limited knowledge of the molecular cues that determine γδ T cell migration toward tumors in vivo. In this study we set out to identify the chemotactic signals that orchestrate tumor infiltration by γδ T cells. We have used the preclinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on γδ TIL recruitment in vivo. We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of γδ TILs in B16 lesions, where they produce IFN-γ and display potent cytotoxic functions. Moreover, CCL2 directed γδ T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing Abs. Strikingly, the lack of γδ TILs in TCRδ-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of γδ T cells. Importantly, we demonstrate that human Vδ1 T cells, but not their Vδ2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver, or breast cancer. This work identifies a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vδ1 T cells in cancer immunotherapy.

show abstract

Section: Discussionsupporting

confidence: 61%

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

Lança

Costa

Gonçalves-Sousa

et al. 2013

The Journal of Immunology

152

130

View full text Add to dashboard Cite

show abstract

“…Many types of tumors can actively prevent T-cell infiltration by modifying gene expression of adhesion molecules such as ICAM-1 and VCAM-1 in vascular endothelial cells (21) or by inducing posttranslational modification of local chemokine signals, including CCL2 (23). Our data are in agreement with several strategies that have been proposed to optimize antitumor T-cell migration by transducing highly targeted, localized chemokine signals at the tumor site.…”

Section: Discussionsupporting

confidence: 88%

Optogenetic control of chemokine receptor signal and T-cell migration

Hyun

Lim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance Precise regulation of chemokine signal is critical for directional migration of cells. In the study of complex cell behavior, it remains difficult to manipulate chemokine activity at precise times and places within living animals, and it is not possible to study different chemokine effects on defined cell types over a range of timescales. Furthermore, a given chemokine can activate multiple chemokine receptors and vice versa. Here we developed a photoactivatable chemokine receptor that can induce highly specific chemokine signals and guide cell migration toward the light stimulation. This work will advance our understanding of the cell migration process with a number of previously unidentified findings. Clinically, our photoactivatable chemokine receptor approach may have broad applications for adoptive cell transfer therapy.

show abstract

“…iNOS) and generating oxidative stress; 31,32 3) inducing the development of Treg; 33-36 and 4) impairing T cell migration by down regulating trafficking related surface molecules. 37-39 In our study, we discovered that VISTA is highly expressed on MDSCs and knockdown of VISTA significantly diminished the MDSC-mediated inhibition of T cell proliferation. This finding suggests that upregulation of VISTA might be an additional mechanism for the immunosuppressive activity of MDSCs, offering a novel strategy of blocking VISTA to normalize MDSCs for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 65%

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

et al. 2018

View full text Add to dashboard Cite

Treatment of acute myeloid leukemia (AML) remains challenging. Enhancement of anti-tumor responses by blocking negative immune regulators is a promising strategy for novel effective leukemia therapeutics. V-domain Ig suppressor of T-cell activation (VISTA) is a recently defined negative regulator mediating immune evasion in cancer. To investigate the effect of VISTA on anti-leukemia immune response in AML, we initiated a study using clinical samples collected from AML patients. Here we report that VISTA is highly expressed on myeloid-derived suppressor cells (MDSCs) in the peripheral blood of AML patients. Both the frequency and intensity of VISTA expression on MDSCs are significantly higher in newly diagnosed AML than in healthy controls. Importantly knockdown of VISTA by specific siRNA potently reduced the MDSCs-mediated inhibition of CD8 T cell activity in AML, suggesting a suppressive effect of VISTA on anti-leukemia T cell response. Furthermore, we observed a strong positive association between MDSC expression of VISTA and T cell expression of PD-1 in AML. These results support the strategy of VISTA-targeted treatment for AML and underscore the strong potential for combined blockade of VISTA and PD-1 pathways in effective leukemia control.

show abstract

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Abstract: Blocking CCL2 nitration in tumors promoted CD8+ influx and reduced tumor growth and prolonged survival in mice when combined with adoptive cell therapy.

Cited by 564 publications

References 73 publications

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

Optogenetic control of chemokine receptor signal and T-cell migration

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

Contact Info

Product

Resources

About