Successful Colon Cancer Eradication after Chemoimmunotherapy Is Associated with Profound Phenotypic Change of Intratumoral Myeloid Cells

Medina-Echeverz, José; Fioravanti, Jessica; Zabala, Maider; Ardaiz, Nuria; Prieto, Jesús; Berraondo, Pedro

doi:10.4049/jimmunol.1001483

Cited by 88 publications

(71 citation statements)

References 55 publications

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“…Nevertheless, tumors progressed rapidly, indicating a state of immunosuppression which is a known characteristic for MC38 tumors. 38 Our results indicate that MeVac FmIL-12 can overcome suppressive signaling and, through activation of the abundant immune effectors, initiate rapid killing of the surrounding tumor cells. Results of this study present MeVac FmIL-12 as a potent therapeutic for …”

Section: Discussionmentioning

confidence: 93%

Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation

et al. 2017

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Combination of oncolytic virotherapy with immunomodulators is emerging as a promising therapeutic strategy for numerous tumor entities. In this study, we developed measles Schwarz vaccine strain vectors encoding immunomodulators to support different phases in the establishment of antitumor immune responses. Therapeutic efficacy of the novel vectors was evaluated in the immunocompetent MC38cea tumor model. We identified vectors encoding an IL-12 fusion protein (MeVac FmIL-12) and an antibody against PD-L1 (MeVac anti-PD-L1), respectively, as the most effective. Treatment of established tumors with MeVac FmIL-12 achieved 90% complete remissions. Profiling of the tumor immune microenvironment revealed activation of a type 1 T helper cell-directed response, with MeVac FmIL-12 ensuring potent early natural killer and effector T cell activation as well as upregulation of the effector cytokines IFN-g and TNF-a. CD8C T cells were found to be essential for the therapeutic efficacy of MeVac FmIL-12. Results of this study present MeVac FmIL-12 as a novel approach for targeted IL-12 delivery and elucidate mechanisms of successful immunovirotherapy.

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Section: Discussionmentioning

confidence: 93%

Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation

et al. 2017

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“…Recently, myeloid-derived suppressor cells were shown to be crucial in controlling tumor microenvironment by suppressing host immune responses (27,28). To study the possible role that they played in our treatment model, we analyzed their presence in liver, spleen, and tumor infiltrates.…”

Section: Sfv-il-12 Treatment Increases Tumor-specific Effector Cd8 T mentioning

confidence: 99%

Eradication of Liver-Implanted Tumors by Semliki Forest Virus Expressing IL-12 Requires Efficient Long-Term Immune Responses

Quetglas

Rodríguez-Madoz

Bezunartea

et al. 2013

The Journal of Immunology

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Semliki Forest virus vectors expressing IL-12 (SFV–IL-12) were shown to induce potent antitumor responses against s.c. MC38 colon adenocarcinomas in immunocompetent mice. However, when MC38 tumors were implanted in liver, where colon tumors usually metastasize, SFV–IL-12 efficacy was significantly reduced. We reasoned that characterization of immune responses against intrahepatic tumors in responder and nonresponder animals could provide useful information for designing more potent antitumor strategies. Remarkably, SFV–IL-12 induced a high percentage of circulating tumor-specific CD8 T cells in all treated animals. Depletion studies showed that these cells were essential for SFV–IL-12 antitumor activity. However, in comparison with nonresponders, tumor-specific cells from responder mice acquired an effector-like phenotype significantly earlier, were recruited more efficiently to the liver, and, importantly, persisted for a longer period of time. All treated mice had high levels of functional specific CD8 T cells at 8 d posttreatment reflected by both in vivo killing and IFN-γ–production assays, but responder animals showed a more avid and persistent IFN-γ response. Interestingly, differences in immune responses between responders and nonresponders seemed to correlate with the immune status of the animals before treatment and were not due to the treatment itself. Mice that rejected tumors were protected against tumor rechallenge, indicating that sustained memory responses are required for an efficacious therapy. Interestingly, tumor-specific CD8 T cells of responder animals showed upregulation of IL-15Rα expression compared with nonresponders. These results suggest that SFV–IL-12 therapy could benefit from the use of strategies that could either upregulate IL-15Rα expression or activate this receptor.

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“…[3][4][5] The alkylating agent cyclophosphamide (CP) is a common chemotherapeutic drug known to adversely cause transient ablation of mature myeloid cell populations. [6][7][8] The recovery phase following CP treatment provides a model of clinical relevance in which to study the processes that control monocyte trafficking.…”

Section: Introductionmentioning

confidence: 99%

CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice

Jacquelin

Licata

Dorgham

et al. 2013

Blood

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Key Points• CX3CR1 mediates monocyte retention in the bone marrow.• Myelorestoration after chemotherapy is controlled by chemokine receptors.The chemokine receptor CCR2 controls the release of Ly6C high monocytes from the bone marrow and their recruitment to sites of inflammation. A second chemokine receptor, CX3CR1, is differentially expressed on monocyte subsets. We examined the role of CX3CR1 in monocyte trafficking during the recovery phase after cyclophosphamide (CP)-induced myeloablation and observed that, in the absence of CCR2, Ly6C high monocytes accumulated in the bone marrow and peripheral reconstitution was severely impaired compared with wild-type (WT) mice. In contrast, in the absence of CX3CR1, Ly6C high monocytes accumulated less rapidly in the marrow but recovered faster in the blood and were more recruited into the spleen, suggesting an opposite action between CCR2 and CX3CR1 in myelorestoration. During the recovery phase, marrow medullar monocytes displayed lower CX3CR1 expression and reduced their adherence to coated CX3CL1. Intravital imaging of the bone marrow showed that CP treatment impacts monocyte trafficking between the parenchyma and the vasculature. Medullar monocytes in CX3CR1 2/2 mice and mice treated with a specific antagonist of CX3CR1 displayed increased mean velocity and displacement and a reduced arrest coefficient compared with WT mice. This study indicates that CX3CR1 reduces the motility of Ly6C high monocytes in the bone marrow and thereby controls their release. (Blood. 2013;122(5):674-683)

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Successful Colon Cancer Eradication after Chemoimmunotherapy Is Associated with Profound Phenotypic Change of Intratumoral Myeloid Cells

Cited by 88 publications

References 55 publications

Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation

Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation

Eradication of Liver-Implanted Tumors by Semliki Forest Virus Expressing IL-12 Requires Efficient Long-Term Immune Responses

CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice

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