Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses

Abstract

There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies.

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy

“…Soluble CD80 mediated intervention of PD-1/PD-L1 axis can restore the activation of both CD4 + and CD8 + T cells with IFN-γ production [34,35]. Virotherapy using oncolytic viruses has been reported to reduce the systemic resistance to PD-1 immunotherapy in an experimental model of liver cancer, thus providing the rationale for combining oncolytic viruses and immune checkpoint blockade in clinical trial [36]. Immune checkpoint receptors are recognized as important players of immune suppression in HCC [37,38].…”

Immunotherapy of Hepatocellular Carcinoma

“…A preclinical study demonstrated oncolytic activity in response to stereotactic body radiation therapy (SBRT) in mice bearing liver tumors [35]. Another study showed immune response to oncolytic adenovirus in mice with lung metastases from a liver cancer [36]. These studies consistently showed a CD8+ T cell response by oncolytic treatment.…”

“…These studies consistently showed a CD8+ T cell response by oncolytic treatment. However, a complete antitumor response could only be elicited in combination with a PD-1 checkpoint inhibitor [35,36].…”

Short Overview of Clinical Trials With Current Immunotherapeutic Tools for Cancer Treatment

“…Показано, что кроме лизиса опухолевых клеток онколитические вирусы стимулируют развитие опухолеспецифичного Т-клеточного ответа, по крайней мере столь же эффективно, как и блокаторы иммунных контрольных точек [89]. С помощью введения в геном онколитического вируса раковых антигенов можно дополнительно повысить эффективность индукции противоопухолевого иммунного ответа.…”