Background SARS-CoV-2 infection leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical data and animal experiments suggest that the renin–angiotensin system (RAS) is involved in the pathogenesis of SARS-CoV-2-induced ALI. Angiotensin-converting enzyme 2 (ACE2) is the functional receptor for SARS-CoV-2 and a crucial negative regulator of RAS. Recombinant ACE2 protein (rACE2) has been demonstrated to play protective role against SARS-CoV and avian influenza-induced ALI, and more relevant, rACE2 inhibits SARS-CoV-2 proliferation in vitro. However, whether rACE2 protects against SARS-CoV-2-induced ALI in animal models and the underlying mechanisms have yet to be elucidated. Methods and Results Here, we demonstrated that the SARS-CoV-2 spike receptor-binding domain (RBD) protein aggravated lipopolysaccharide (LPS)-induced ALI in mice. SARS-CoV-2 spike RBD protein directly binds and downregulated ACE2, leading to an elevation in angiotensin (Ang) II. AngII further increased the NOX1/2 through AT1R, subsequently causing oxidative stress and uncontrolled inflammation and eventually resulting in ALI/ARDS. Importantly, rACE2 remarkably reversed SARS-CoV-2 spike RBD protein-induced ALI by directly binding SARS-CoV-2 spike RBD protein, cleaving AngI or cleaving AngII. Conclusion This study is the first to prove that rACE2 plays a protective role against SARS-CoV-2 spike RBD protein-aggravated LPS-induced ALI in an animal model and illustrate the mechanism by which the ACE2-AngII-AT1R-NOX1/2 axis might contribute to SARS-CoV-2-induced ALI.

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Cancer immunology research has been centered on how to generate anti-tumor immunity. However, unambiguous clinical evidence has shown that in advanced cancer patients, the tumors induce extensive immune system disorder, i.e., systemic inflammation. In this study, we investigated the impact of systemic inflammation on survival and efficacy of immunotherapy. We found that systemic inflammation drives mice health deterioration during disease progression to late stage and treating the systemic inflammation, with no need to inhibit tumor growth, improves health condition and extends survival. These findings suggest that systemic inflammation in advanced cancer might be an important therapeutic target. Methods 7-week old BALB/c mice were inoculated with 1 x106 C26 tumor cells subcutaneously. Mice body weight and health condition were measured starting 7 days after tumor inoculation. At various time points, peripheral blood was drawn, and immune cells was analyzed with flow cytometry; serum cytokines were measured with mouse cytokine array. Tumor bearing mice were treated with anti-PD1 antibody and anti-inflammation drugs and the treatment effect was monitored. Results Localized tumor growth progressively induces host immune system disorder with increase of Gr1+ cell population and decrease of CD3+ cell population in peripheral blood. When mice began to lose body weight, the cell percentage imbalance was enlarged (Gr1+ %: Naïve 7.90 ± 0.727 vs tumor 72.15 ± 4.143, p<0.0001; CD3+%: Naïve 41.18±2.023 vs tumor 9.18 ±0.249, p<0.0001). The immune cell imbalance along health deterioration (>15% body weight loss) further exacerbates (Gr1+ %: early 72.15 ± 4.143 vs late 93.83 ± 1.971, p=0.0032; CD3+ %: early 9.18±0.249 vs late 6.25±1.085, p=0.0392). In addition, pro-inflammatory cytokines such as IL-1, IL-6 and TNF-a increase expression in mouse serum accompanying health condition deterioration. More importantly, therapeutic interventions with anti-inflammation drug Ketorolac or by depletion of Gr1+ inflammatory cells, could reverse the deterioration process and significantly increase mice survival. Interestingly, when combined with anti-PD-1 antibody, treating systemic inflammation enhances the anti-tumor efficacy of the antibody. Conclusions Progressive systemic inflammation characterized by severe immune cell imbalance and overexpression of multiple inflammatory cytokines drives the rapid overall health deterioration of late stage cancer. Treating the systemic inflammation not only reverses health deterioration but also significantly increases survival. Therefore, targeting systemic inflammation might be a promising approach to the treatment of late stage cancer. Citation Format: Lingbing Zhang, Gennie Liu. Treatment of systemic inflammation significantly improves survival in a murine model that recapitulates the rapid health deterioration of advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5590.

It’s well known that tumor growth induces immune system dysfunction, and cancer immunology has been focused on studying anti-tumor immunity, however the impact of the immune dysfunction on health of the host has not been studied. In this study, we investigate the immune system change and its impact on the host under tumor development from tumor establishment to overall health deterioration and death. We identified significant and multifaceted abnormalities of the immune system which triggers cancer cachexia onset and development. Thus, we propose a new term tumor-induced immune disorder (TID) for these abnormalities. We defined the TID by two parameters: multiple inflammatory cytokines expression; loss of balance and normal behavior of immune cells. Furthermore, we took efforts to explore potential treatments to correct the TID. We have identified a novel immunomodulator, i.e., (R)-ketorolac which can suppress expression of multiple inflammatory cytokines, and consistently, it can fully remove symptoms of cancer cachexia. Thus, we established the causative relationship between TID and cachexia. Interestingly cachectic mice treated by (R)-ketorolac are not only cured of cachexia thus avoid imminent death but also tolerate and respond to full dose anti-tumor chemotherapies. These findings have important clinical implications given majority of late-stage cancer patients with cachexia cannot tolerate chemotherapies and other anti-tumor treatments, thus get stuck in the treatment dilemma. Thus, this study points out a new direction to develop cancer immunotherapies by targeting and correcting the TID, which can not only prevent imminent death by curing cancer cachexia, but also provide opportunities for patients to receive and respond to anti-tumor treatments. Citation Format: Lingbing Zhang. Tumor-induced immune disorder: the root cause of cancer cachexia and therapeutic target [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A11.