RESUMEN
Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.
RESUMEN
The novel coronavirus disease 2019 (COVID-19) epidemic, which was first identified in Wuhan, China in December 2019, has rapidly spread all over China and across the world. By the end of February 2020, the epidemic outside Hubei province in China has been well controlled, yet the next wave of transmission in other countries may have just begun. A retrospective modeling of the transmission dynamics would provide insights into the epidemiological characteristics of the disease and evaluation of the effectiveness of the strict measures that have been taken by central and local governments of China. Using a refined susceptible-exposed-infectious-removed (SEIR) transmission model and a new strategy of model fitting, we were able to estimate model parameters in a dynamic manner. The resulting parameter estimation can well reflect the prevention policy scenarios. Our simulation results with different degrees of government control suggest that the strictly enforced quarantine and travel ban have significantly decreased the otherwise uncontrollable spread of the disease. Our results suggest similar measures should be considered by other countries that are of high risk of COVID-19 outbreak. SummaryO_ST_ABSBackgroundC_ST_ABSThe novel coronavirus disease 2019 (COVID-19) epidemic, which was first reported in Wuhan and rapidly spread across the world, has been well controlled in China but is only starting to take off in other countries. Here we provide a retrospective modelling analysis of the transmission dynamics in China and evaluated the effectiveness of the strict government control strategies. MethodsWe considerably refined the original susceptible-exposed-infectious-removed (SEIR) transmission model, and used the publicly available data from Jan 13rd to Feb 29th for model fitting and parameter estimation in a dynamic manner considering effect of prevention policies. We then used the estimated model parameters to simulate the epidemic trend and transmission risk of the disease with various degrees of government control. FindingsThe severity rate and the fatality rate remain unchanged during the whole epidemic. While government intervention had a moderate effect on the incubation rate ({sigma}), the recovered rate ({gamma}) endured several fold increase. Strikingly, a significant decrease in the infectious rate ({beta}) was observed. Without government control, peak infected cases in Wuhan would reach 7.78 million (70% of the whole population) and total deaths could reach 319000 based on the current mortality rate (4.1%). InterpretationOur simulation results with different degrees of government control suggest that the strictly enforced quarantine and travel ban have significantly decreased the otherwise uncontrollable spread of the disease. Our results suggest similar measures should be considered by other countries that are of high risk of COVID-19 outbreak. FundingThe National Natural Science Foundation of China (21877060). Research in contextO_ST_ABSEvidence before the studyC_ST_ABSA global outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been posing significant threats to public health worldwide. By the end of February 2020, 87645 confirmed cases are reported around the world, including 7330 severe cases and 2994 fatalities. We searched PubMed and preprint archive for papers published up to Feb 29th, 2020, using keywords "COVID-19", "SARS-CoV-2", "2019-nCoV", and "novel coronavirus." We found several researches on the transmission dynamics of COVID-19; however, only one preprint predicted the effect of government intervention in China with incomplete epidemiological data. Added value of this studySince the epidemic is already close to its end in China except Wuhan city, we have the opportunity to carry out a relatively complete retrospective analysis. We optimized the SEIR model using a dynamic fitting approach, taking into account the government measures and reached a much more precise fitting of the data comparing to other studies published. We showed that the severity rate and the fatality rate remain unchanged during the whole epidemic, suggesting the only effective way to control the disease is to control the number of infections. While government intervention had a moderate effect on the incubation rate ({sigma}), it is essential for increasing the recovered rate ({gamma}), and for decreasing and stabilizing the infectious rate ({beta}). We also simulated the scenarios with various degrees of government control which could be a useful tool to predict the necessity of government intervention. An interactive online application was made available to the public on Feb 24th, 2020. Implications of all the available evidenceThe COVID-19 outbreak has already been effectively controlled in China; however, the risk of rapid global explosion is extremely high due to the high transmissive rate of the SARS-CoV-2 virus. The quarantine measures adopted by the Chinese government are essential for the control of the COVID-19 epidemic.