TMPRSS2 is the link between lung cancer and pneumonia caused by SARS-CoV-2 infection

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TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. 

The study findings were published on a preprint server: Research Square, and is currently being peer reviewed. https://www.researchsquare.com/article/rs-740479/v3

In five lung adenocarcinoma (LUAD) genomics datasets, we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, and clinical prognosis in LUAD by the bioinformatics approach.

We found that TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures.

It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD.

We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD dataset we collected. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1.

Discussion

As a pivotal molecule in the regulation of SARS-CoV-2 invading human host cells, TMPRSS2 is attracting massive attention in the current SARS-CoV-2 pandemic.32–34

Because SARS-CoV-2 has and is infecting large numbers of people, including many cancer patients, an investigation into the role of TMPRSS2 in cancer may provide valuable advice for treating cancer patients infected with SARS-CoV-2.

Previous studies of TMPRSS2 in cancer mainly focused on its oncogenic role in prostate cancer.6–8 

In this study, we focused on LUAD, considering that it is the most common histological type in lung cancer and that the lungs are the primary organ SARS-CoV-2 attacks. In contrast to its oncogenic role in prostate cancer, TMPRSS2 plays a tumor suppressive role in LUAD, as we have provided abundant evidence.

First, TMPRSS2 downregulation correlates with elevated activities of many oncogenic pathways in LUAD, including cell cycle, mismatch repair, p53, and ECM signaling.

Second, TMPRSS2 downregulation correlates with increased tumor cell proliferation, stemness, genomic instability, and ITH in LUAD. Finally, TMPRSS2 downregulation is associated with tumor advancement and worse survival in LUAD. Furthermore, both in vitro and in vivo experiments demonstrated that TMPRSS2 downregulation markedly promoted the proliferation and invasion capacity of LUAD cells, supporting the tumor suppressor role of TMPRSS2 in LUAD.

Our bioinformatics analysis revealed significant negative associations between TMPRSS2 expression and immune signatures, including both immune-stimulatory and immune-inhibitory signatures, in LUAD (Figure 1a). Nevertheless, TMPRSS2 expression tended to have a stronger negative correlation with immune-inhibitory signatures than with immune-stimulatory signatures in LUAD (Figure 1b).

The significant different levels of correlations of immune-stimulatory and immune-inhibitory signatures with TMPRSS2 expression could be a factor responsible for the worse prognosis in LUAD patients with TMPRSS2 deficiency. Furthermore, the associations between TMPRSS2 and tumor immunity in LUAD were completely verified by both in vitro and in vivo experiments.

That is, knockdown of TMPRSS2 significantly increased tumor immunogenicity and immune cell infiltration in LUAD. On the other hand, both computational and experimental data showed that TMPRSS2 downregulation significantly enhanced PD-L1 expression in LUAD.

Because both inflamed tumor microenvironment and PD-L1 expression are determinants of cancer response to immunotherapy,35 TMPRSS2-depleted LUAD would respond better to immunotherapy than TMPRSS2-wildtype LUAD. This was supported by our in vivo experiments showing that TMPRSS2-knockdown tumors were more sensitive to the PD-1/PD-L1 inhibitor.

Thus, TMPRSS2 downregulation is a positive biomarker of immunotherapy for LUAD. In addition, because TMPRSS2 downregulation often occurs in advanced LUAD, it indicates that advanced LUAD could benefit more from immunotherapy than early-stage LUAD.

TMPRSS2 inhibition has been indicated as a strategy for preventing and treating SARS-CoV-2 infection for the crucial role of TMPRSS2 in the SARS-CoV-2 invasion.33,36 However, our data suggest that this strategy may not be a good option for lung cancer patients in terms of the tumor suppressor role of TMPRSS2 in LUAD.

Interestingly, we found that TMPRSS2 displayed significantly higher expression levels in non-smoker than in smoker LUAD patients in four LUAD cohorts in which related data were available (Student’s t test, p < 0.05, FC > 1.5) (Figure 6a). This result indicates that non-smoker LUAD patients could be more susceptible to SARS-CoV-2 infection than smoker LUAD patients.

As expected, non-smoker LUAD patients had significantly lower TMB and antitumor immunity than smoker LUAD patients (Figure 6b), consistent with findings from previous studies.37,38

In conclusion, TMPRSS2 is a tumor suppressor in LUAD, as evidenced by its downregulation correlated with increased genomic instability and ITH, tumor progression, and unfavorable clinical outcomes in LUAD. However, TMPRSS2 downregulation is a positive biomarker of immunotherapy for LUAD. Our data provide implications in the connection between lung cancer and pneumonia caused by SARS-CoV-2 infection.

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