Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer

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Abstract

// Lily Francis 1, 2, * , Zong Sheng Guo 1, 2, * , Zuqiang Liu 1, 2 , Roshni Ravindranathan 1, 2 , Julie A. Urban 1, 2 , Magesh Sathaiah 1, 2 , Deepa Magge 1, 2 , Pawel Kalinski 1, 2, 3, 4 , David L. Bartlett 1, 2 1 University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 2 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 3 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 4 Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA * These authors have contributed equally to this work Correspondence to: David L. Bartlett, e-mail: bartlettdl@upmc.edu Pawel Kalinski, e-mail: kalinskip@upmc.edu Keywords: oncolytic virus, immunotherapy, tumor microenvironment, chemokine, pharmaceutical modulation Received: September 29, 2015     Accepted: February 20, 2016     Published: March 04, 2016 ABSTRACT An oncolytic poxvirus such as vvDD-CXCL11 can generate potent systemic antitumor immunity as well as targeted oncolysis, yet the antitumor effect is limited probably due to limited homing to and suppressed activity of tumor-specific adaptive immune cells in the tumor microenvironment (TME). We reasoned that a chemokine modulating (CKM) drug cocktail, consisting of IFN-α, poly I:C, and a COX-2 inhibitor, may skew the chemokine (CK) and cytokine profile into a favorable one in the TME, and this pharmaceutical modulation would enhance both the trafficking into and function of antitumor immune cells in the TME, thus increasing therapeutic efficacy of the oncolytic virus. In this study we show for the first time in vivo that the CKM modulates the CK microenvironment but it does not modulate antitumor immunity by itself in a MC38 colon cancer model. Sequential treatment with the virus and then CKM results in the upregulation of Th1-attracting CKs and reduction of T reg -attracting CKs (CCL22 and CXCL12), concurrent with enhanced trafficking of tumor-specific CD8 + T cells and NK cells into the TME, thus resulting in the most significant antitumor activity and long term survival of tumor-bearing mice. This novel combined regimen, with the oncolytic virus (vvDD-CXCL11) inducing direct oncolysis and eliciting potent antitumor immunity, and the CKM inducing a favorable chemokine profile in the TME that promotes the trafficking and function of antitumor Tc1/Th1 and NK cells, may have great utility for oncolytic immunotherapy for cancer.

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