Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.

Background Recent literature reports a strong thrombotic tendency in patients hospitalized for a Covid‐19 infection. This characteristic is quite unusual and seems specific to Covid‐19 infections, especially in their severe form. Viral infections can trigger acquired thrombophilia which can then lead to thrombotic complications. We investigate for the presence of acquired thrombophilia, which could participate in this phenomenon and report their prevalence. We also wonder if these thrombophilias participate in the bad prognosis of severe Covid‐19 infections. Methods and Results In 89 consecutive patients hospitalized for Covid‐19 infection we found a 20% prevalence of protein S deficiency and a very high ie.: 72% prevalence of antiphospholipid antibodies: mainly lupus anticoagulant. The presence of PS deficiency or antiphospholipid antibodies was not linked with a prolonged aPTT nor with D‐dimer, fibrinogen or C‐reactive protein concentrations. These coagulation abnormalities are also not linked with thrombotic clinical events occurring during hospitalization nor with mortality. Conclusions We assess a high prevalence of positive tests detecting thrombophilia in Covid‐19 infections. However, in our series, these acquired thrombophilias are not correlated with the severity of the disease nor with the occurrence of thrombotic events. Albeit the strong thrombotic tendency in Covid‐19 infections, the presence of frequent acquired thrombophilia may be part of the inflammation storm of Covid‐19 disease and should not systematically modify our strategy on prophylactic anticoagulant treatment which is already revised upwards in this pathology.

Although it is generally accepted that dietary fiber is health promoting, the underlying immunological and molecular mechanisms are not well defined, especially with respect to cellulose, the most ubiquitous dietary fiber. Here, the impact of dietary cellulose on intestinal microbiota, immune responses and gene expression in health and disease was examined. Lack of dietary cellulose disrupted the age-related diversification of the intestinal microbiota, which subsequently remained in an immature state. Interestingly, one of the most affected microbial genera was Alistipes which is equipped with enzymes to degrade cellulose. Absence of cellulose changed the microbial metabolome, skewed intestinal immune responses toward inflammation, altered the gene expression of intestinal epithelial cells and mice showed increased sensitivity to colitis induction. In contrast, mice with a defined microbiota including A. finegoldii showed enhanced colonic expression of intestinal IL-22 and Reg3γ restoring intestinal barrier function. This study supports the epidemiological observations and adds a causal explanation for the health promoting effects of the most common biopolymer on earth.

Summary Introduction Activated partial thromboplastin time (aPTT) is a routine clotting assay that is widely used to globally screen for coagulation abnormalities. It is commonly admitted that a prolonged test result, may trigger the need for specific assays to be performed, particularly factor measurement. However, the sensitivity of aPTT reagents to deficiencies of clotting factors varies. Methods We evaluated, according to the recommendation of the CLSI H47‐A2 guideline, the responsiveness to single factor levels of five aPTT reagents by using factor‐deficient plasmas spiked with a calibration plasma to produce individual factor activities ranging from <1 to ~100 Unit (U)/dL. Test results were expressed as the sample‐to‐control ratio, the latter was defined as the clotting time obtained in the calibration plasma containing ~100 U/dL factor activity. The factor activity producing a prolongation of aPTT above the upper limit of its specific normal range (in ratio) was assigned as the factor responsiveness in U/dL to that reagent. Results Responsiveness ranged from 34 to 47 U/dL to FVIII:C, from 18 to 57 U/dL to FIX, from 38 to 52 U/dL to FXI, from 29 to 50 U/dL to FXII, from 40 and 59 U/dL to FV, from 7.5 to 49 U/dL to FX, and from 9.1 to 10.5 U/dL to FII. Conclusions These results suggest that the sensitivity of the tested aPTT reagents to single factor deficiency is highly variable. Moreover, for one given aPTT reagent, its sensitivity was very different depending on the deficient factor. This must be considered when analyzing clinical materials.

No abstract