Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Type 1 Interferon

• Respiratory syncytial virus

• Metastasis

• Breast cancer

Main Findings

The immunosuppressive environment of cancer increases susceptibility to viral infections, but how these infections change the lung environment and influence lung metastasis is lesser known. In this preprint, Farias et al. examined the interaction between respiratory syncytial virus (RSV) infection and breast cancer metastasis in a mouse model, focusing on the type I interferon (IFN) response in lung metastatic initiation and progression. Type I IFN is secreted by alveolar macrophages and is typically induced early in response to RSV. In cancer, type I IFN plays a key role in anti-tumor immunity and tumor suppression; however, prolonged expression can lead to immune exhaustion or tolerance diminishing its tumor-suppressive effect.

Faria et al. intranasally infected mice with RSV prior to injection with mouse mammary tumor virus-polyoma middle T antigen cells (MMTV-PyMT), a primary breast carcinoma cell line representing earlier stages of breast cancer progression. The authors found that the number of lung metastatic nodules were reduced, but had similar size, compared to mice without RSV infection.  Depletion of neutrophils, monocytes, natural killer cells, and T cells did not affect metastasis, and metastatic cells did not alter the immune response to RSV.

To explore the role of type I IFN, the authors analysed IFNα's effects on the lung environment. Intranasal IFNα treatment before cancer cell injection mimicked RSV’s anti-metastatic effect, but this was lost with UV-inactivated RSV, which cannot induce IFN. IFN receptor knockout mice, where only cancer cells could respond to IFNα, showed no difference in metastasis, suggesting IFNα modifies the lung environment rather than directly affecting cancer cells. Single-cell RNA sequencing and interaction strength analysis revealed that lung epithelial cells, rather than direct IFNα effects on tumor cells, may drive the observed anti-metastatic activity.

Limitations

• Depleting one cell type at a time may have masked cell interactions important for overall effect to reduce metastasis

• The experimental design lacks a primary tumor model for pre-metastatic niche generation and for Ifnar1 -/- cancer model testing

• No measurement of IFNα at end-point of experiment to correlate with findings

• No mechanistic studies (e.g. transcriptomics/proteomics) of lung microenvironment post-RSV infection or IFNα treatment

• No discussed mechanism for how epithelial cells in the tumor-microenvironment may reduce metastasis

• No long-term survival outcome data

• Needs investigation across more cancer types and other lung-specific viruses

• No human studies

Significance/Novelty

This preprint highlights the important role of early IFNα on the pre-metastatic lung environment in preventing metastatic colonization. The focus on intranasal administration is relevant to lung metastasis and differs from traditional intra-peritoneal/subcutaneous IFNα treatments. While this may have important clinical implications, the pleiotropic effect of IFN raises uncertainty about sustained administration, timing and dosage of IFN which require further investigation.

Preprint rating

• Scientific quality: 4

• Novelty: 4

• Significance:4

Credit

Reviewed by Lisha Jeena, Centre for Immuno-oncology, Oxford, as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.

The author declares no conflict of interests in relation to their involvement in the review.