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Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma.

ABSTRACT: Successful immunotherapy for melanoma depends on the recruitment of effector CD8⁺ T cells to the tumor microenvironment. Factors contributing to T cell regulation in melanoma have recently been recognized, including the stimulator of interferon genes (STING). Agents that can activate STING or enhance T cell infiltration into established tumors have become an important focus for further clinical development. Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus, type 1 (HSV-1) encoding granulocyte-macrophage colony stimulating factor (GM-CSF) and is approved for the treatment of melanoma and has shown therapeutic activity in murine tumors known to express high levels of STING. The mechanism of action for T-VEC has not been fully elucidated but is thought to include induction of immunogenic cell death (ICD) and activation of host anti-tumor immunity. Thus, we sought to investigate how T-VEC mediates anti-tumor activity in a melanoma model. To determine if T-VEC induced ICD we established the relative sensitivity of a panel of melanoma cell lines to T-VEC oncolysis. Following T-VEC infection in vitro, melanoma cell lines released of HMGB1, ATP, and translocated ecto-calreticulin. To identify potential mediators of this effect, we found that melanoma cell sensitivity to T-VEC was inversely related to STING expression. CRISPR/Cas9-STING knockout was also associated with increased T-VEC cell killing. In the D4M3A melanoma, which has low expression of STING and is resistant to PD-1 blockade therapy, T-VEC was able to induce therapeutic responses in both injected and non-injected tumors and demonstrated recruitment of viral- and tumor-antigen specific CD8⁺ T cells, and induction of a pro-inflammatory gene signature at both injected and non-injected tumors. These data suggest that T-VEC induces ICD in-vitro and promotes tumor immunity and can induce therapeutic responses in anti-PD-1-refractory, low STING expressing melanoma.

SUBMITTER: Bommareddy PK

PROVIDER: S-EPMC6527276 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma.

Bommareddy Praveen K PK Zloza Andrew A Rabkin Samuel D SD Kaufman Howard L HL

Oncoimmunology 20190407 7

Successful immunotherapy for melanoma depends on the recruitment of effector CD8<sup>+</sup> T cells to the tumor microenvironment. Factors contributing to T cell regulation in melanoma have recently been recognized, including the stimulator of interferon genes (STING). Agents that can activate STING or enhance T cell infiltration into established tumors have become an important focus for further clinical development. Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus, type 1 ...[more]

PMID: 31143509

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Project description:Background: Oncolytic viruses (OVs) are emerging as potent inducers of immunogenic cell death (ICD), releasing danger-associated molecular patterns (DAMPs) that induce potent anticancer immunity. Oncolytic Newcastle disease virus (NDV) has been shown to educe ICD in both glioma and lung cancer cells. The objective of this study is to investigate whether oncolytic NDV induces ICD in melanoma cells and how it is regulated. Methods: Various time points were actuated to check the expression and release of ICD markers induced by NDV strain, NDV/FMW in melanoma cell lines. The expression and release of ICD markers induced by oncolytic NDV strain, NDV/FMW, in melanoma cell lines at various time points were determined. Surface-exposed calreticulin (CRT) was inspected by confocal imaging. The supernatants of NDV/FMW infected cells were collected and concentrated for the determination of ATP secretion by ELISA, HMGB1, and HSP70/90 expression by immunoblot (IB) analysis. Pharmacological inhibition of apoptosis, autophagy, necroptosis, ER Stress, and STAT3 (signal transducer and activator of transcription 3) was achieved by treatment with small molecule inhibitors. Melanoma cell lines stably depleted of STAT3 were established with lentiviral constructs. Supernatants from NDV-infected cells were intratumorally injected to mice bearing melanoma cells-derived tumors. Results: Oncolytic NDV induced CRT exposure, the release of HMGB1 and HSP70/90 as well as secretion of ATP in melanoma cells. Inhibition of apoptosis, autophagy, necroptosis or ER stress attenuated NDV/FMW-induced release of HMGB1 and HSP70/90. Moreover, NDV/FMW-induced ICD markers in melanoma cells were also suppressed by either treatment with a STAT3 inhibitor or shRNA-mediated depletion of STAT3. Of translational importance, treatment of mice bearing melanoma cells-derived tumors with supernatants from NDV/FMW-infected cells significantly inhibited tumor growth. Conclusions: Our data authenticate that oncolytic NDV/FMW might be a potent inducer of ICD in melanoma cells, which is amalgamated with several forms of cell death. We also show that STAT3 plays a role in NDV/FMW-induced ICD in melanoma cells. Together, our data highlight oncolytic NDV as propitious for cancer therapeutics by stimulatingan anti-melanoma immune response.

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Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma.

Publications

Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma.

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