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Objective To investigate the role of tumor draining lymph nodes (TDLN) in the generation of memory CD8+ T cells under the context of neoadjuvant anti-PD-L1 therapy. Methods A mouse transplanted model of CT26/MC38-OVA colon cancer was established to recapitulate clinic neoadjuvant anti-PD-L1 therapy, and then the tumor masses and TDLN were removed in 15 d after transplantation. On day 30 after surgery, the effect of TDLN on the formation of immune memory was assessed under the condition of neoadjuvant PD-L1 antibody therapy by tumor re-challenge. The effect of neoadjuvant PD-L1 on tumor-specific CD8+ T cells was investigated by adoptive transfer CD45.1+ OT-Ⅰ cells. The distribution and phenotype of CD45+ CD8+T cells in various tissues were determined by flow cytometry at the time of surgery (effector phase) and 30 d after surgery (memory phase). Results The tumor mass was reduced significantly after receiving neoadjuvant anti-PD-L1 therapy (P < 0.05). After tumor re-challenge, tumor growth was significantly slowed in the mice treated with neoadjuvant PD-L antibody, whereas TDLN resection accelerated the tumor growth (P < 0.05). However, long-term survival of tumor re-challenge showed that all tumors were eventually subsided, whether or not the mice treated with neoadjuvant PD-L antibody. The results of adoptive reinjection indicated that the number of CD45.1+ CD8+ T cells being stored in TDLN and no-draining lymph nodes (NLN) was the highest (P < 0.05). Tcm (T central memory) cells and Trm (tissue-resident memory) cells were mainly distributed in TDLN and NLN in memory phase (P < 0.05). The distribution and memory phenotype of CD45.1+ CD8+ T cells in TDLN and NLN had no obvous changes after neoadjuvant anti-PD-L1 therapy. Conclusion TDLN is the primary site for the storage of memory CD8+ T cells, but under the condition of neoadjuvant PD-L1 antibody treatment, TDLN resection does not affect their long-term anti-tumor immunity.

Simple Summary: Polyphenol compounds are important physiological activity materials that resist corrosion and oxidation, can be maintained in a state of freshness, and can be used safely, among other advantages. In China, the most important cereal crop is sorghum, which is an important raw material for brewing. However, sorghum stalks are usually considered to have no value and are thrown away or burned, resulting in environmental pollution and the possible waste of a usable resource. Notably, the sorghum stalk contains an abundance of polyphenols that exhibit great development potential as unconventional resources. However, studies on sorghum stalks with respect to their polyphenol compounds and their effects on in vitro rumen fermentation in goats have been relatively rare to date. Accordingly, in the present study, six types of sorghum (Sorghum bicolor L. Moench) varieties used for brewing traditional Chinese liquor were selected, and we compared their stalks in terms of their chemical composition, polyphenol compounds, antioxidant activity, and effects on in vitro rumen fermentation in goats. Our findings provide new details regarding the use of this unconventional feed for goats, as well as theories for developing this kind of resource for use as ruminant feed. The aim of the study was to examine the differences in the chemical composition, polyphenol compounds, antioxidant activity, and in vitro rumen fermentation among six varieties of sorghum stalks. The results show that maoliangnuo 1 (M1) contained a higher (p < 0.05) level of dry matter, and jinzhong 405 (J4) contained a higher (p < 0.05) level of crude protein content. The concentrations of neutral detergent fiber, acid detergent fiber, and cellulose were significantly higher (p < 0.05) in stalk jinliangnuo (JN). The levels of chlorogenic acid, homoorientin, isovitexin, vitexin, rhoifolin, genistin, quercetin, apigenin, aloe emodin, emodin, and total polyphenols were all significantly (p < 0.05) higher in maohongnuo 6 (M6) than in the other stalks. Moreover, stalk M6 contained higher (p < 0.05) levels of total antioxidant capacity (TAC), glutathione peroxidase (GPX), catalase (CAT), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging capacity. There were significant (p < 0.05) positive correlations between total polyphenols and TAC, superoxide dismutase, GPX, CAT, and DPPH free-radical scavenging capacity. The total gas production was significantly (p < 0.05) influenced by the sorghum stalk variety and incubation time. Stalk J4 displayed higher values for the (p < 0.05) immediately soluble fraction and the potential extent of gas production, while stalk M6 exhibited a significantly lower (p < 0.05) insoluble fraction level. Furthermore, stalk M6 exhibited a significantly higher level of (p < 0.05) ruminal fluid propionic acid, but its level of butyric acid and its ratio of acetic acid to propionic acid were both significantly lower (p < 0.05). Taken together, the results reported in this paper indicate that the chemical composition, polyphenol compounds, antioxidant activity, and in vitro rumen fermentation all vary greatly among different varieties of sorghum stalks. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis( Mtb) is a pathogen of tuberculosis, and 1-deoxy-ID-xylulose- 5-phosphate reductoisomerase (DXR) is a key rate-limiting enzyme in the metabolism of Mtb, so it is thought to be a potential antibacterial target. This paper collects 35 fosmidomycin derivatives with in vitro inhibitory activity against Mycobacterium tuberculosis1-deoxy-D-xylulose-5-phosphate reductoisomerase (mtDXR), conducts a three dimensional quantitative structure-activity relationship between them by using comparative molecular field analysis ( CoMFA ) and comparative molecular similarity indices analysis (CoMSIA), and establishes corresponding models. The results show that, for CoMFA model, the best principal component value n is 7, the cross validation coefficient q² is 0.601, and the correlation coefficient r² is 0.979. For CoMSIA model, the best principalcomponent value n is 8, the cross validation coefficient q² is 0.609, and the correlation coefficient r² is 0.983. The data show that both CoMFA and CoMSIA models have good predictability. Meanwhile, the molecular docking method is introduced to further investigate the non-bonding interaction between these small molecule inhibitors of fosmidomycin and amino acid residues on target active sites. Combined with contour maps of 3D-QSAR, the modification areas of molecular structure of these compounds are determined which can be processed and optimized. On the basis of these work, this paper designs 14 new fosmidomycin derivatives, predicts their activity, and obtains a new compound 27m with higher predictive activity. The conclusions derived from this paper provide a theoretical basis and important reference for the further development of new mtDXR inhibitors. [ABSTRACT FROM AUTHOR]

Anti–PD-1/PD-L1 therapy, either by anti–PD-1 antibody or anti–PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8+ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8+ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200+ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200+ T cells positively related to a favorable clinical outcome to anti–PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200+ CTLs are essential for efficacious anti–PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200+ CTLs and found that these cells are enriched for tumor antigen–specific CTLs and have antitumor effector functions. Coinoculation of CD200+ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200+ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200+ CTLs in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic. Identifying responders: A challenge for the field of cancer immunotherapy is identifying which patients will respond to immune checkpoint blockade treatments such as anti-PD-1 or anti-PD-L1. Here, Wang et al. showed using murine tumor models that CD200+ CD8+ T cells were crucial for the efficacy of anti-PD-1/PD-L1 therapy. These CD200+ cytotoxic T lymphocytes had a unique chromatin landscape and possessed superior anti-tumor effector functions as compared to CD200- CD8+ T cells. Further, the authors showed, using data from multiple patient cohorts, that CD200+ T cells could predict immunotherapy efficacy, suggesting that this cell population could serve as a potential marker in the clinic. —CM [ABSTRACT FROM AUTHOR]

Anti-PD-(L)1 therapy has shown great efficacy in some patients with cancer. However, a significant proportion of patients with cancer do not respond to it. Another unmet clinical need for anti-PD-(L)1 therapy is the dynamic monitoring of treatment effects. Therefore, identifying biomarkers that can stratify potential responders before PD-(L)1 treatment and timely monitoring of the efficacy of PD-(L)1 treatment are crucial in the clinical setting. The identification of biomarkers by liquid biopsy has attracted considerable attention. Among the identified biomarkers, circulating T cells are one of the most promising because of their indispensable contribution to anti-PD-(L)1 therapy. The present review aimed to thoroughly explore the potential of circulating T cells as biomarkers of anti-PD-(L)1 therapy and its advantages and limitations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision, (Copyright © 2024 Hou, Yang, Xie, Zhu and Zha.)