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STING Sensing of Murine Cytomegalovirus Alters the Tumor Microenvironment to Promote Antitumor Immunity
Nicole A Wilski1, Colby Stotesbury1, Christina Del Casale1
1Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
Abstract:
CMV has been proposed to play a role in cancer progression and invasiveness. However, CMV has been increasingly studied as a cancer vaccine vector, and multiple groups, including ours, have reported that the virus can drive antitumor immunity in certain models. Our previous work revealed that intratumoral injections of wild-type murine CMV (MCMV) into B16-F0 melanomas caused tumor growth delay in part by using a viral chemokine to recruit macrophages that were subsequently infected. We now show that MCMV acts as a STING agonist in the tumor. MCMV infection of tumors in STING-deficient mice resulted in normal recruitment of macrophages to the tumor, but poor recruitment of CD8+ T cells, reduced production of inflammatory cytokines and chemokines, and no delay in tumor growth. In vitro, expression of type I IFN was dependent on both STING and the type I IFNR. Moreover, type I IFN alone was sufficient to induce cytokine and chemokine production by macrophages and B16 tumor cells, suggesting that the major role for STING activation was to produce type I IFN. Critically, viral infection of wild-type macrophages alone was sufficient to restore tumor growth delay in STING-deficient animals. Overall, these data show that MCMV infection and sensing in tumor-associated macrophages through STING signaling is sufficient to promote antitumor immune responses in the B16-F0 melanoma model.
Insights
Murine cytomegalovirus (MCMV) acts as a STING agonist, promoting antitumor immunity. MCMV infection of tumor-associated macrophages via STING signaling is sufficient to enhance anti-melanoma immune responses.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Cytomegalovirus (CMV) is investigated for its role in cancer progression and as a cancer vaccine vector.
- Previous research indicated that murine CMV (MCMV) can elicit antitumor immunity.
- MCMV's mechanism in recruiting macrophages to melanomas was previously linked to tumor growth delay.
Purpose of the Study:
- To elucidate the mechanism by which MCMV infection promotes antitumor immunity in B16-F0 melanomas.
- To investigate the role of STING (STimulator of INterferon Genes) signaling in MCMV-mediated antitumor responses.
- To determine if MCMV acts as a STING agonist and its downstream effects on immune cell recruitment and cytokine production.
Main Methods:
- Intratumoral injection of wild-type MCMV into B16-F0 melanomas in both wild-type and STING-deficient mice.
- Analysis of immune cell infiltration (macrophages, CD8+ T cells) within tumors.
- Measurement of inflammatory cytokine and chemokine production.
- In vitro studies assessing type I Interferon (IFN) expression and its dependence on STING and type I IFNR.
- Experiments involving viral infection of wild-type macrophages in STING-deficient animals.
Main Results:
- MCMV infection in STING-deficient mice led to normal macrophage recruitment but impaired CD8+ T cell infiltration, reduced cytokine/chemokine production, and abolished tumor growth delay.
- In vitro, type I IFN expression was dependent on both STING and the type I IFN receptor (IFNR).
- Type I IFN alone induced cytokine and chemokine production by macrophages and tumor cells, highlighting its central role.
- Infection of wild-type macrophages alone rescued the tumor growth delay phenotype in STING-deficient mice.
Conclusions:
- MCMV functions as a STING agonist within the tumor microenvironment.
- STING sensing of MCMV infection in tumor-associated macrophages is crucial for initiating robust antitumor immune responses.
- This STING-macrophage axis is sufficient to promote anti-melanoma immunity, involving type I IFN production and subsequent immune cell recruitment.
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