Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy

Boivin, Gaël; Ancey, Pierre‐Benoit; Silly, Romain Vuillefroy de; Kalambaden, Pradeep; Contat, Caroline; Petit, Benoît; Ollivier, Jonathan; Bourhis, Jean; Meylan, Etienne; Vozenin, Marie-Catherine

doi:10.1080/2162402x.2021.1876597

Cited by 16 publications

(15 citation statements)

References 46 publications

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“…As a previous study [ 21 ], we used anti-Ly6G antibody to deplete Ly6G + neutrophils and explore their role in the aggravation of UVB-caused skin damage in Gsdme −/− mice. In UVB-challenged Gsdme −/− and WT mice, we determined levels of CD11b + Gr-1 + (Gr-1 here was used to avoid false negative signals) cells in peripheral blood after anti-Ly6G antibody injection.…”

Section: Resultsmentioning

confidence: 99%

GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils

et al. 2022

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Gasdermin E (GSDME)-mediated pyroptosis is induced in keratinocytes of UVB-challenged skin. The role of GSDME in UVB-caused skin damage remains unknown. To explore the role of GSDME in UVB-induced skin inflammation. We compared differences in skin appearance, histological features, keratinocyte death modalities, infiltration of immune cells, and levels of some inflammatory cytokines between Gsdme−/− mice and wild type (WT) mice after UVB exposure. We explored whether keratinocytes contribute to GSDME deficiency-caused aggravation of UVB-induced skin inflammation in GSDME knockdown keratinocyte cultured in vitro and keratinocyte-specific Gsdme conditional knockout mice. We used anti-Ly6G antibody to deplete neutrophils and explore their role in UVB-caused skin damage. Skin damage and neutrophils infiltration were aggravated in UVB-challenged Gsdme−/− mice, compared with UVB-challenged WT mice. Apoptosis and necroptosis, which were initiated together with GSDME-mediated pyroptosis in UVB-challenged WT mice, were not enhanced in UVB-challenged Gsdme−/− mice. Neutrophils activation indicators and its recruiting cytokines were increased in skin tissue of UVB-challenged Gsdme−/− mice. However, GSDME knockdown did not lead to the further increase of mRNA and secretion of TNF-α and IL-6 in UVB-challenged keratinocytes. Skin damage was not aggravated in UVB-challenged Gsdme cKO mice. Neutrophils depletion alleviated UVB-caused skin damage in WT mice and Gsdme−/− mice, and eliminated its aggravation in Gsdme−/− mice. This study demonstrates that GSDME plays a restrictive role in UVB-induced skin damage through inhibiting excessive recruitment and activation of neutrophils in the immune microenvironment in UVB-caused skin inflammation. However, keratinocytes might not contribute to this restrictive function.

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Section: Resultsmentioning

confidence: 99%

GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils

et al. 2022

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“…Notably, evidence has verified that anti-Ly6G antibody-mediated neutrophil depletion may lead to an improvement of the RT efficacy. 196 , 197 These data suggest that neutrophils play a crucial role in the tumor microenvironment following RT which may promotes the conversion of N1 to N2. Thus, targeting neutrophils and their immunosuppressive effector molecules, TGFβ and nicotinamide phosphoribosyltransferase (NAMPT) might be crucial to reversing immunosuppression.…”

Section: Rationale Of Irtmentioning

confidence: 89%

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Zhang

Liu

Chen

et al. 2022

Sig Transduct Target Ther

183

141

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Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.

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“…The radiation-induced regulation of the immune microenvironment is a double-edged sword that renders the body immune in a very delicate balance between immune activation and immunosuppression (4). In addition to the activation of the innate and adaptive immune systems, RT can also induce immunosuppression responses such as the polarization of macrophages with the M2 phenotype (21,22), neutrophils with the N2 phenotype (23)(24)(25)(26), and accumulation of myeloid-derived suppressor cells (MDSCs) (27,28). These cells generally induce immunosuppressive effects via PD-L1 expression and other mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review

Wang¹,

Lei²,

Yang³

et al. 2022

Ann Transl Med

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Background and Objective: Radiotherapy (RT) is one of the fundamental anti-cancer regimens by means of inducing in situ tumor vaccination and driving a systemic anti-tumor immune response. It can affect the tumor microenvironment (TME) components consisting of blood vessels, immunocytes, fibroblasts, and extracellular matrix (ECM), and might subsequently suppress anti-tumor immunity through expression of molecules such as programmed death ligand-1 (PD-L1). Immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1)/PD-L1 therapies, have been regarded as effective in the reinvigoration of the immune system and another major cancer treatment. Experimentally, combination of RT and ICIs therapy shows a greater synergistic effect than either therapy alone.Methods: We performed a narrative review of the literature in the PubMed database. The research string comprised various combinations of "radiotherapy", "programmed death-ligand 1", "microenvironment", "exosome", "myeloid cell", "tumor cell", "tumor immunity". The database was searched independently by two authors. A third reviewer mediated any discordance of the results of the two screeners.Key Content and Findings: RT upregulates PD-L1 expression in tumor cells, tumor-derived exosomes (TEXs), myeloid-derived suppressor cells (MDSCs), and macrophages. The signaling pathways correlated to PD-L1 expression in tumor cells include the DNA damage signaling pathway, epidermal growth factor receptor (EGFR) pathway, interferon gamma (IFN-γ) pathway, cGAS-STING pathway, and JAK/STATs pathway.Conclusions: PD-L1 upregulation post-RT is found not only in tumor cells but also in the TME and is one of the mechanisms of tumor evasion. Therefore, further studies are necessary to fully comprehend this biological process. Meanwhile, combination of therapies has been shown to be effective, and novel approaches are to be developed as adjuvant to RT and ICIs therapy.

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Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy

Cited by 16 publications

References 46 publications

GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils

GSDME deficiency leads to the aggravation of UVB-induced skin inflammation through enhancing recruitment and activation of neutrophils

Radiotherapy combined with immunotherapy: the dawn of cancer treatment

Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review

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