Oncolytic adenovirus ORCA-010 activates pro-inflammatory myeloid cells and facilitates T cell recruitment and activation by PD-1 blockade in melanoma

Ioanna Emilova Milenova, Marta Lopez Gonzalez, Dafne Carolina Alves Quixabeira, João Manuel Santos, Victor Cervera-Carrascon, Wenliang Dong, Akseli Hemminki, Victor W van Beusechem, Rieneke van de Ven, Tanja D de Gruijl

Research output: Contribution to journalArticleAcademicpeer-review

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 CD8α+ 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 CD8α+ 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.

Original languageEnglish
Pages (from-to)178-191
Number of pages14
JournalHuman Gene Therapy
Volume32
Issue number3-4
Early online date20 Jan 2021
DOIs
Publication statusPublished - Feb 2021

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