In the December 26th issue of "War Heart Daily", we interpreted 10 documents, focusing on: tumor microenvironment, ammonia, hyaluronic acid , sulfur-containing amino acids, CHD6-TMEM65, immunotherapy , tumor flora, cancer metastasis, neoadjuvant chemotherapy, adagrasiib, sotorasib, reprotinib.
Cell Sub-Journal: Ammonia accumulation in the colorectal cancer microenvironment can lead to T cell exhaustion
Cell Metabolism——[31.373]
① In the metastatic colorectal cancer (CRC) mouse model TripleMut, CRC histologically progresses more severely, metastasizes, and is resistant to immunotherapy; ② Ammonia metabolism genes are down-regulated in TripleMut mice CRC, and a large amount of ammonia accumulates in the tumor, inhibiting the T cell transsulfurization pathway and causing T cell oxidative stress; ③ Ammonia treatment or feeding high ammonium acetate food causes T cell exhaustion in vivo and in vitro, and promotes CRC growth; ④ Clearing ammonia using ornithine and other methods can activate T cells, inhibit CRC cell growth in vivo and in vitro, and enhance the anti-PD-L1 therapeutic effect; ⑤ Ammonia metabolism genes are downregulated in tumors of CRC patients, and serum ammonia levels are increased, which is associated with tumor metastasis and worse prognosis of immune checkpoint therapy.
[Editor's comment]
Changes in cell metabolism are one of the hallmarks of tumors, affecting the tumor microenvironment (TME), immune landscape and treatment response. The TME is a local environment that is hypoxic, nutrient-poor, and has high concentrations of metabolic waste products. Ammonia is one of the nitrogen sources of tumor cells, but high levels of ammonia are also cytotoxic. There is a lack of previous research on the impact of ammonia in the TME on the progression and treatment of colorectal cancer (CRC). Researchers from the University of Michigan recently published a research article in Cell Metabolism, revealing that ammonia accumulated in the CRC microenvironment causes T cell exhaustion and immunosuppression, confirming that ammonia clearance can be used as an auxiliary means for anti-PD-L1 therapy. (@ Mustard)
[Original information]
Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer
2022-12-16, doi: 10.1016/j.cmet.2022.11.013
Cell sub-issue: How hyaluronic acid reshapes the colorectal cancer microenvironment
Cancer Cell——[38.585]
① In tumors of colorectal cancer (CRC) patients, low expression of atypical protein kinase C (aPKC) increases the synthesis and accumulation of hyaluronic acid (HA), and the tumors are highly mesenchymal and have poor prognosis; ② Knockdown of aPKC in CRC mice or tumor organoids leads to an increase in HA and activation of tumor-associated fibroblasts (CAF); ③ HA promotes the heterogeneity of epithelial cells in tumors and the emergence of tumor fetal metaplasia cells through activated CAF, enhancing the invasiveness of CRC; ④ Hyaluronidase administration can degrade intratumoral HA in mice, inhibit CRC mesenchymalization and liver metastasis, promote the recruitment of B cells, and CD8+ T cells, relieve immune suppression, and enhance the effect of immune checkpoint blockade therapy.
[Editor’s comment]
Colorectal cancer (CRC) of the CMS4 subtype has activation of tumor-associated fibroblasts (CAF) and acquisition of mesenchymal phenotype, which rejects immune cells and is resistant to immune checkpoint blockade therapy. At present, the understanding of the mechanisms of tumor-mesenchymal transition and CAF activation is still insufficient, and there are also difficulties in the development of related targeted therapies. Some researchers have therefore turned their attention to relevant components in the extracellular matrix of the tumor microenvironment (TME). Researchers from Weill Cornell Medical College of Cornell University in the United States recently published a research article in Cancer Cell and found that low expression of atypical protein kinase C in CRC drives the accumulation of hyaluronic acid and CAF activation and mesenchymalization. Hyaluronidase can target the degradation of hyaluronic acid in the TME, and combined with immune checkpoint inhibitors can enhance the anti-tumor effect. This study provides new ideas for the treatment of mesenchymal colorectal cancer.(@ Mustard)
【Original information】
Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer
2022-12-15, doi: 10.1016/j.ccell.2022.11.016
Peking University First Hospital: Reducing the intake of sulfur-containing amino acids may enhance colon cancer immunotherapy
Cancer Research——[13.312]
① The level of hydrogen sulfide (H2S) in the tumors of colon cancer patients increased significantly, which was related to the decrease in the ratio of CD8+ T/Treg cells; ② H2S promotes the differentiation of CD4+ T cells into Treg, enhances ENO1 (enolase 1) sulfhydryl modification of Cys119 promotes Treg activation, and at the same time enhances the transcription factor ELK4 Thiolation of Cys25 promotes AAK1 expression to inhibit the migration of CD8+ T cells, forming an immunosuppressive tumor microenvironment; ③ In mouse models with defects in key enzymes for H2S synthesis or sulfur-containing amino acid restricted diet (SARD), H2S levels in colon cancer subcutaneous transplant tumors are reduced, the CD8+ T/Treg ratio is increased, and the tumors are more sensitive to immune checkpoint inhibitors.
[Editor’s comment]
Some patients with colon cancer cannot benefit from immune checkpoint blockade therapy, which may be related to the immunosuppressive tumor microenvironment. Targeting unique metabolites in the tumor microenvironment may be a potential way to break immune suppression. Both intestinal epithelial cells and intestinal microbes can use sulfur-containing amino acids in the diet to produce hydrogen sulfide (H2S). Previous studies have shown that H2S is related to intestinal inflammation and colon cancer chemotherapy resistance. High-sulfur microbial diet scores are also related to the risk of early-onset colon adenoma and colon cancer. Peking University First Hospital Chen Shanwen’s team recently published a research article in Cancer Research, revealing the mechanism by which H2S participates in forming the immunosuppressive microenvironment of colon cancer, and found that a restricted diet of sulfur-containing amino acids can be used as a potential dietary method to enhance the effect of colon cancer immunotherapy. (@ Mustard)
[Original information]
Hydrogen sulfide creates a favorable immune microenvironment for colon cancer
2022-12-16, doi: 10.1158/0008-5472.CAN-22-1837
Sun Yat-sen University : CHD6-TMEM65 axis may be involved in colorectal cancer
Cell Discovery——[38.079]
① CHD6 is highly expressed in colorectal cancer, and knockdown can inhibit tumor cell proliferation, migration, invasion, and tumorigenesis. Intestinal-specific knockout can reduce tumorigenesis in AOM/DSS model mice; ② Abnormal EGF signaling inhibits GSK3β activity, inhibits phosphorylation of by CHD6, and blocks CHD6 ubiquitination and degradation mediated by E3 ligase FBXW7; ③ CHD6 binds to the Wnt signaling transcription factor TCF4 to promote the transcription of TMEM65, an inner mitochondrial membrane protein involved in ATP production and mitochondrial dynamics; ④ The CHD6 promoter contains TCF4 and β-catenin binding sites; ⑤ Combination of Wnt inhibitors and anti-EGFR inhibits CRC xenograft growth.
[Editor's comment]
The chromatin helicase DNA-binding protein (CHD) family plays an important role in regulating gene transcription. This family is related to cancer diseases, but the role of its family members in tumorigenesis still needs further exploration. The team of Li Menghong and Liu Qingxin of Sun Yat-sen University published an article in Cell Discovery and found that CHD6 regulates the mitochondrial inner membrane protein TMEM65 through EGF and Wnt signaling, thereby promoting the development of colorectal cancer. Targeting the CHD6-TMEM65 axis may be used to prevent and treat tumors.(@ Zhangtai Liu)
[Original information]
The chromatin remodeler CHD6 promotes colorectal cancer development by regulating TMEM65-mediated mitochondrial dynamics via EGF and Wnt signaling
2022-12-06, doi: 10.1038/s41421-022-00478-z
Cell sub-publication of Beizhuan Team: How does intestinal flora affect the effect of neoadjuvant chemotherapy for rectal cancer?
Cancer Cell——[38.585]
① Analyzed stool samples from patients with locally advanced rectal cancer (LARC) before and after neoadjuvant chemotherapy (nCRT) and found that the diversity of bacterial flora decreased after nCRT; ② Bacteroides vulgaris -mediated nucleotide biosynthesis is associated with nCRT resistance in LARC patients, weakening the response to nCRT in LARC patients, and non-responsive tumors are characterized by upregulation of genes related to DNA repair and nucleoside transport; ③ Nucleoside supplements or intragastric administration of Bacteroides vulgaris protect cancer cells from damage caused by 5-fluorouracil or radiation therapy; ④ Analysis of 2205 serum samples from 735 patients showed that uric acid is a potential prognostic indicator for patients with LARC receiving nCRT.
[Editor’s comment]
Preoperative neoadjuvant chemotherapy (nCRT) is the standard treatment for patients with locally advanced rectal cancer (LARC), but patients have variable responses to treatment, and the factors involved require further study. Academician Zhan Qimin from Peking University Cancer Hospital (Beijing Institute of Cancer Prevention and Treatment ) and Professor Wang Weihu collaborated to publish an article in Cancer Cell, which found that nucleotide biosynthesis mediated by Bacteroides vulgatus can weaken the response of LARC patients to nCRT, and also revealed that uric acid is a potential prognostic indicator for LARC patients receiving nCRT. (@ Zhangtai Liu)
[Original information]
Gut microbiota-mediated nucleotide synthesis attenuates the response to neoadjuvant chemoradiotherapy in rectal cancer
2022-12-22, doi: 10.1016/j.ccell.2022.11.013
West Lake University Cai Shang’s team: The new role of intratumoral flora in cancer metastasis (review)
Trends in Cell Biology——[21.167]
① Cancer metastasis is a key link in the development of malignant tumors, which is determined by the characteristics of tumor cells themselves and external environmental factors; ② As an important indicator of tumor environment sensors, tumor pathological types, drug response, and prognosis, intratumoral flora plays an important role in the tumor progression of multiple cancer types; ③ Intratumoral flora exists in tumor tissues with low abundance and low diversity, mainly located within cells; ④ The extracellular and extracellular localization of bacteria within tumors makes them ideal carriers for drug delivery to reverse intercellular and intracellular signaling networks; ⑤ Modulating intratumoral flora can reduce cancer metastasis, prevent cancer development and reprogram immune responses.
[Editor’s comment]
Cancer metastasis is one of the main causes of death in cancer patients. In recent years, intratumoral flora has been identified as an indispensable tumor component and may functionally regulate various aspects of metastasis. The new discovery of intratumoral flora has opened up new ways to study cancer progression and clinical cancer management. Recently, Cai Shang's team at Westlake University published a review in Trends in Cell Biology, summarizing the latest progress in the emerging role of intratumoral microbiota in cancer metastasis, and discussed the challenges and significance of cancer treatment.(@元儿)
【Original information】
Emerging roles of intratumor microbiota in cancer metastasis
2022-12-13, doi: 10.1016/j.tcb.2022.11.007
How the microbiome affects tumor immunotherapy (review)
Trends in Immunology——[19.709]
① The intestinal microbiome can regulate the host's anti-tumor immune response, affect tumor development, and affect the effectiveness of tumor immunotherapy such as immune checkpoint inhibitors (ICI) and adoptive T cell therapy (including CAR-T cell therapy); ② Direct contact between microorganisms and immune cells mediated by microbial -related molecular patterns, antigen mimicry, etc. can induce dendritic cells, , and CD8+ T cells to kill tumors; ③ Metabolites produced by the flora, such as short-chain fatty acids , creatinine, secondary bile acids, etc., can enhance or inhibit the efficacy of ICI; ④ Fecal bacterial transplantation, living biological drugs, prebiotics , etc. can adjust the composition of intestinal microorganisms or can be used to enhance the anti-tumor effect of ICI.
[Editor's comment]
The microbiome is a key influencing factor in health and disease. Currently, changes in the composition and function of the microbiome are also considered potential markers of tumors, affecting the occurrence, progression, and treatment of tumors. Researchers from the British microbiome therapy company Microbiotica and the Wellcome Sanger Institute recently published a review article in Trends in Immunology, systematically summarizing the ways in which the intestinal microbiome affects the effect of tumor immunotherapy, and summarizing potential methods to improve the structure of the intestinal microbiome to promote tumor immunotherapy. (@ Mustard)
[Original information]
The heightened importance of the microbiome in cancer immunotherapy
2022-12-01, doi: 10.1016/j.it.2022.11.002
NEJM: KRAS G12C inhibitor adagrasib can be used to treat advanced colorectal cancer
New England Journal of Medicine——[176.079]
① Included in KRAS For patients with advanced metastatic colorectal cancer with G12C mutations, 44 patients were treated with adagrasib monotherapy (600 mg orally twice daily), and 32 patients were combined with and cetuximab ; ② The median follow-up time of the single-agent and combination treatment groups were 20.1 months and 17.5 months, respectively, and the objective response rates were 19% and 46%, respectively; ③ The median duration of response in the single-agent and combination therapy groups were 4.3 months and 7.6 months respectively, and the median progression-free survival was 5.6 months and 6.9 months respectively; ④ The incidence rates of grade 3 or 4 treatment-related adverse events in the single-agent and combination therapy groups were 34% and 16% respectively, and no grade 5 adverse events were observed.
[Editor’s comment]
3%-4% of colorectal cancer patients carry the KRAS G12C mutation, and their survival outcomes are worse than those with other KRAS mutations. Adagrasib is an inhibitor of KRAS G12C mutation under development by Mirati Therapeutics. It can selectively and irreversibly covalently bind to the KRAS G12C site to inactivate it. Preliminary data suggest adarasibu shows clinical activity in patients with colorectal cancer. Recently, the New England Journal of Medicine published the results of the phase 1b/2 clinical trial of KRYSTAL-1, confirming that in patients with advanced metastatic colorectal cancer with KRAS G12C mutations, adagrasiib showed sustained anti-tumor activity and good safety, with or without cetuximab. The results of this trial support further large-scale clinical trials and may provide more effective treatment options for patients with KRAS-mutated colorectal cancer.(@ Mustard)
[Original information]
Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C
2022-12-21, doi: 10.1056/NEJMoa2212419
NEJM: KRAS The G12C inhibitor sotoraxib can be used to treat advanced pancreatic cancer
New England Journal of Medicine——[176.079]
① Including 38 cases of KRAS Patients with locally advanced or metastatic pancreatic cancer with G12C mutations had received at least one systemic therapy in the past. 12 and 26 patients were enrolled in the phase 1 and phase 2 trials respectively. All patients were orally treated with 960 mg of sotoraxib daily; ② The median treatment duration was 18 weeks, no patient had complete response, 8 cases (21%) had partial response, and the median response time was 1.5 months; ③ In 30 Shrinking of target tumor lesions was observed in 79% of patients; ④ Overall, the median progression-free survival was 4.0 months and the median overall survival was 6.9 months; ⑤ 16 treatment-related adverse events were reported, 6 of which were grade 3 adverse events, and there were no treatment-related deaths or treatment interruptions.
[Editor’s comment]
About 90% of pancreatic ductal adenocarcinomas contain KRAS mutations. The KARS G12C mutation occurs in approximately 1%-2% of pancreatic cancers . Sotorasib, a small molecule inhibitor that specifically and irreversibly binds KRAS G12C, has been approved for the treatment of KRAS G12C-mutated non-small cell lung cancer , but its safety and efficacy in patients with KRAS G12C-mutated pancreatic cancer are unclear. Recently, the New England Journal of Medicine published the results of the Phase 1/2 clinical trial of CodeBreaK 100, which confirmed that in patients with KRAS G12C-mutated advanced pancreatic cancer who had previously received systemic therapy, sotorasiib alone showed clinically significant anti-cancer activity and acceptable safety, providing a new feasible strategy for targeted therapy of KRAS-mutated advanced pancreatic cancer. (@ Mustard)
[Original information]
Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer
2022-12-21, doi: 10.1056/NEJMoa2208470
Ripotinib in the treatment of advanced gastrointestinal stromal tumors
Clinical Cancer Research——[13.801]
① 129 GIST patients were randomly divided into two groups, 85 took 150 mg of repotinib daily, and 44 took placebo daily; ② The median PFS of patients in the repotinib group was 6.3 months, which was significantly better than the 1.0 month of patients in the placebo group. There was no significant difference in objective response rate (ORR) between the two groups of patients (9% vs. 0%); ③ The median OS of patients in the repotinib group and the placebo group were 15.1 months and 6.6 months respectively, and no formal statistical comparison was conducted; ④ The most common adverse events in patients in the repotinib group included: alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, hand-foot syndrome, and vomiting.
[Editor’s Comment]
On March 15, 2020, the FDA approved Ripretinib for the treatment of advanced gastrointestinal stromal tumors (GIST) that have received more than 3 kinase inhibitors including imatinib . A latest article in Clinical Cancer Research summarizes this approval.(@aluba)
【Original information】
FDA Approval Summary: Ripretinib for advanced gastrointestinal stromal tumor
2022-12-09, doi: 10.1158/1078-0432.CCR-22-2400
Thanks to the creators of this daily report: Mustard, Zhang Tailiu, Zzz, Paihuabaobao, aluba
Click to read the daily reports of the past 10 days:
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12-17 | New clinical evidence: Intermittent fasting helps improve diabetes, safe and effective
12-16 | Drinking water makes you fat? Predisposition to obesity may be related to intestinal type
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