Abstract
Prostate cancers are considered “cold” tumors characterized by minimal T cell infiltrates, absence of a type I interferon (IFN) signature, and the presence of immunosuppressive cells. This non-inflamed phenotype is likely responsible for the lack of sensitivity of prostate cancer patients to immune checkpoint blockade (ICB) therapy. Oncolytic virus therapy can potentially overcome this resistance to immunotherapy in prostate cancers by transforming cold tumors into “hot,” immune cell-infiltrated tumors. We investigated whether the combination of intratumoral oncolytic reovirus, followed by targeted blockade of Programmed cell death protein 1 (PD-1) checkpoint inhibition and/or the immunomodulatory CD73/Adenosine system can enhance anti-tumor immunity. Treatment of subcutaneous TRAMP-C2 prostate tumors with combined intratumoral reovirus and anti-PD-1 or anti-CD73 antibody significantly enhanced survival of mice compared with reovirus or either antibody therapy alone. Only combination therapy led to rejection of pre-established tumors and protection from tumor re-challenge. This therapeutic effect was dependent on CD4+ T cells and natural killer (NK) cells. NanoString immune profiling of tumors confirmed that reovirus increased tumor immune cell infiltration and revealed an upregulation of the immune-regulatory receptor, B- and T-lymphocyte attenuator (BTLA). This expression of BTLA on innate antigen-presenting cells (APCs) and its ligand, Herpesvirus entry mediator (HVEM), on T cells from reovirus-infected tumors was in keeping with a role for the HVEM-BTLA pathway in promoting the potent anti-tumor memory response observed.
Highlights
Cancer immunotherapy with monoclonal antibodies against immune checkpoints has revolutionized the treatment of patients affected by certain cancer types,[1,2] clinical trials in patients with prostate cancer have shown them to be less sensitive to this therapeutic approach.[3,4,5] These findings have fueled significant research efforts to identify pre-existing and acquired mechanisms of resistance to immune checkpoint blockade (ICB)
TRAMP-C2 Cells Are Highly Susceptible to In Vitro ReovirusInduced Oncolysis In order to use the TRAMP-C2-immunocompetent prostate cancer model for studies investigating the synergistic effect of combining reovirus oncolytic virotherapy with ICB, we first tested in vitro the susceptibility of TRAMP-C2 cells to reovirus infection and compared this with the known reovirus-susceptible prostate cell lines PC-3 and DU145
This study using oncolytic reovirus in combination with ICB adds to the growing evidence that the combination of oncolytic viruses (OVs) and ICB is an effective therapy for re-sensitizing immune checkpoint-resistant tumors into immunotherapy-responsive tumors.[38,39,40]
Summary
Cancer immunotherapy with monoclonal antibodies (mAbs) against immune checkpoints has revolutionized the treatment of patients affected by certain cancer types,[1,2] clinical trials in patients with prostate cancer have shown them to be less sensitive to this therapeutic approach.[3,4,5] These findings have fueled significant research efforts to identify pre-existing and acquired mechanisms of resistance to immune checkpoint blockade (ICB). Like other OVs, reovirus is thought to mediate anti-tumor activity through a dual mechanism of selective replication within and lysis of infected cancer cells, while simultaneously inducing host antitumor immunity.[13,14,15] Tumor lysis by OVs induces immunological “danger” signals and releases tumor antigens (immunogenic cell death [ICD]).[16] Reovirus can infect and activate dendritic cells (DCs) directly, which, upon their maturation, activate natural killer (NK) and T cells to kill cancer cells.[17] The efficacy of reovirus as a therapeutic agent has been demonstrated by our group and others in numerous preclinical and clinical trials.[18,19,20,21,22] Most importantly, intralesional reovirus injections in murine cancer models and human patients have resulted in an inflammatory effect with significant T cell infiltration. Early-phase monotherapy clinical trials of reovirus have failed to demonstrate appreciable clinical efficacy in the form of objective and durable responses, highlighting the need to augment reovirus’s therapeutic potency
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