Oncolytic Adenovirus ORCA-010 Activates Proinflammatory Myeloid Cells and Facilitates T Cell Recruitment and Activation by PD-1 Blockade in Melanoma

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Milenova , I , Gonzalez , M L , Quixabeira , D C A , Santos , J M , Cervera-Carrascon , V , Dong , W , Hemminki , A , van Beusechem , V W , van de Ven , R & de Gruijl , T D 2021 , ' Oncolytic Adenovirus ORCA-010 Activates Proinflammatory Myeloid Cells and Facilitates T Cell Recruitment and Activation by PD-1 Blockade in Melanoma ' , Human Gene Therapy , vol. 32 , no. 3-4 , pp. 178-191 . https://doi.org/10.1089/hum.2020.277

Title: Oncolytic Adenovirus ORCA-010 Activates Proinflammatory Myeloid Cells and Facilitates T Cell Recruitment and Activation by PD-1 Blockade in Melanoma
Author: Milenova, Ioanna; Gonzalez, Marta Lopez; Quixabeira, Dafne C. A.; Santos, Joao Manuel; Cervera-Carrascon, Victor; Dong, Wenliang; Hemminki, Akseli; van Beusechem, Victor W.; van de Ven, Rieneke; de Gruijl, Tanja D.
Contributor organization: Research Programs Unit
TRIMM - Translational Immunology Research Program
Faculty of Medicine
University of Helsinki
Department of Pathology
Department of Oncology
HUS Comprehensive Cancer Center
Date: 2021-02-01
Language: eng
Number of pages: 14
Belongs to series: Human Gene Therapy
ISSN: 1043-0342
DOI: https://doi.org/10.1089/hum.2020.277
URI: http://hdl.handle.net/10138/328961
Abstract: Immune checkpoint inhibitors have advanced the treatment of melanoma. Nevertheless, a majority of patients are resistant, or develop resistance, to immune checkpoint blockade, which may be related to prevailing immune suppression by myeloid regulatory cells in the tumor microenvironment (TME). ORCA-010 is a novel oncolytic adenovirus that selectively replicates in, and lyses, cancer cells. We previously showed that ORCA-010 can activate melanoma-exposed conventional dendritic cells (cDCs). To study the effect of ORCA-010 on melanoma-conditioned macrophage development, we used an in vitro co-culture model of human monocytes with melanoma cell lines. We observed a selective survival and polarization of monocytes into M2-like macrophages (CD14(+)CD80(-)CD163(+)) in co-cultures with cell lines that expressed macrophage colony-stimulating factor. Oncolysis of these melanoma cell lines, effected by ORCA-010, activated the resulting macrophages and converted them to a more proinflammatory state, evidenced by higher levels of PD-L1, CD80, and CD86 and an enhanced capacity to prime allogenic T cells and induce a type-1 T cell response. To assess the effect of ORCA-010 on myeloid subset distribution and activation in vivo, ORCA-010 was intratumorally injected and tested for T cell activation and recruitment in the human adenovirus nonpermissive B16-OVA mouse melanoma model. While systemic PD-1 blockade in this model in itself did not modulate myeloid or T cell subset distribution and activation, when it was preceded by i.t. injection of ORCA-010, this induced an increased rate and activation state of CD8 alpha(+) cDC1, both in the TME and in the spleen. Observed increased rates of activated CD8(+) T cells, expressing CD69 and PD-1, were related to both increased CD8 alpha(+) cDC1 rates and M1/M2 shifts in tumor and spleen. In conclusion, the myeloid modulatory properties of ORCA-010 in melanoma, resulting in recruitment and activation of T cells, could enhance the antitumor efficacy of PD-1 blockade.
Subject: oncolytic adenovirus
macrophages
T cells
immune checkpoint inhibition
melanoma
318 Medical biotechnology
11832 Microbiology and virology
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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