The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In ...particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.
Immune checkpoint inhibitors have had a major impact on cancer treatment. Gut microbiota plays a major role in the cancer microenvironment, affecting treatment response. The gut microbiota is highly ...individual, and varies with factors, such as age and race. Gut microbiota composition in Japanese cancer patients and the efficacy of immunotherapy remain unknown.
We investigated the gut microbiota of 26 patients with solid tumors prior to immune checkpoint inhibitor monotherapy to identify bacteria involved in the efficacy of these drugs and immune-related adverse events (irAEs).
The genera
and
were relatively common in the group showing efficacy towards the anti-PD-1 antibody treatment (effective group). The proportions of
(P = 0.022) and
(P = 0.049) were significantly higher in the effective group than in the ineffective group. In addition, the proportion of
(P = 0.033) was significantly higher in the ineffective group. Next, they were divided into irAE and non-irAE groups. The proportions of
(P = 0.001) and
(P = 0.001) were significantly higher in the group with irAEs than in those without, while the proportions of
(P = 0.013) and the unclassified
(P = 0.027) were significantly higher in the group without irAEs than those with. Furthermore, within the Effective group,
and
(both P = 0.001) were more abundant in the subgroup with irAEs than in those without them. In contrast,
(P = 0.021) and
(P= 0.033) were statistically significantly more common in those without irAEs.
Our Study suggests that the analysis of the gut microbiota may provide future predictive markers for the efficacy of cancer immunotherapy or the selection of candidates for fecal transplantation for cancer immunotherapy.
Cancer of unknown primary (CUP) is a malignant tumor without a known primary lesion with a frequency of 3-5%. It can be divided into favorable and unfavorable prognosis subsets. While recommended ...treatments are available for the former group, there is no established treatment for the latter. Here, we report the effective treatment of a 32-year-old woman with p16-positive squamous cell CUP with pembrolizumab plus 5-fluorouracil and cisplatin therapy.
A 32-year-old woman presented with metastatic lesions in the liver, lung, bone, cervical region, abdominal region, and pelvic lymph nodes. She was diagnosed with p16-positive squamous cell carcinoma of unknown primary origin. The patient received pembrolizumab plus 5-fluorouracil and cisplatin therapy, which markedly reduced the metastasis and improved her Eastern Cooperative Oncology Group performance status after two courses.
This case report highlights the potential of pembrolizumab plus 5-fluorouracil and cisplatin therapy for treating CUP with an unfavorable prognosis. p16 positivity is worth examining for squamous cell carcinoma of unknown primary origin, and if present, this therapy should be considered a promising treatment option.
Splenic abscesses are rare, but can be life-threatening. Antibiotics, percutaneous drainage and splenectomy are the usual treatment options. However, there is no ideal algorithm for choosing among ...these options. A man in his 60 s presented with 10 days of left upper quadrant pain and abdominal distension. Computed tomography (CT) scan of the abdomen revealed a splenic abscess measuring 15 cm in diameter. Transesophageal echocardiography confirmed the diagnosis of infectious endocarditis. Ultrasound-guided percutaneous drainage was performed and Streptococcus anginosus grew in cultures of both blood and intrasplenic fluid. The patient was treated with intravenous antibiotics and continuous drainage for 8 weeks. The abscess cavity nearly disappeared on follow-up CT scan. Percutaneous drainage should be considered for a solitary unilocular splenic abscess even if the abscess is large.
Introduction
Programmed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. ...PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.
Methods
In total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.
Results
PD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.
Conclusion
Quantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method.
Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible before initiating systemic ...chemotherapy, owing to the liver's diffuse metastatic involvement. Moreover, an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.
The patient, a man in his 50s, presented with progressive fatigue and severe jaundice. Computed tomography revealed multiple hepatic masses with thickened walls in the sigmoid colon, which was pathologically confirmed as a well-differentiated adenocarcinoma. No
or
mutations were detected. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 2. Biliary drainage was impossible due to the absence of a dilated bile duct, and panitumumab monotherapy was promptly initiated. Subsequently, the bilirubin level decreased and then normalized, and the patient's PS improved to zero ECOG score after four cycles of therapy without significant adverse events.
Anti-EGFR antibody monotherapy is a safe and effective treatment for
wild-type CRC and hepatic metastases with severe hyperbilirubinemia.
RNA activation (RNAa) is an uncharacterized mechanism of transcriptional activation mediated by small RNAs, such as microRNAs (miRNAs). A critical issue in RNAa research is that it is difficult to ...distinguish between changes in gene expression caused indirectly by post-transcriptional regulation and direct induction of gene expression by RNAa. Therefore, in this study, we seek to identify a key factor involved in RNAa, using the induction of ZMYND10 by miR-34a as a system to evaluate RNAa. We identify the positive transcription elongation factors CDK9 and DDX21, which form a complex with nuclear AGO and TNRC6A, as important transcriptional activators of RNAa. In addition, we find that inhibition of DDX21 suppresses RNAa by miR-34a and other miRNAs without inhibiting post-transcriptional regulation. Our findings reveal a strong connection between RNAa and release of paused Pol II, facilitating RNAa research by making it possible to separately analyze post-transcriptional regulation and RNAa.
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•miR-34a and paRNA-targeting siRNAs induce ZMYND10 mRNA by RNA activation•AGO2 and TNRC6A form a complex with DDX21-CDK9 in nucleus•miRNA-AGO-TNRC6A complex releases Pol II pausing via DDX21-CDK9•An example of gene regulation mechanism by widely expressed paRNA
RNAa is a mechanism of transcriptional activation mediated by small RNAs. Ohno et al. identify the positive transcription elongation factors CDK9 and DDX21, which form a complex with nuclear AGO and TNRC6A, as transcriptional activators of RNAa. The findings reveal a connection between RNAa and release of paused Pol II.
Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%–30%; consequently, prognostic and immune‐related adverse ...event (irAE) predictors are being explored. The programmed cell death protein 1 (PD‐1) receptor occupancy (RO) of PD‐1 inhibitors depends on the number of peripheral blood lymphocytes and their PD‐1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD‐1 inhibition affects each T‐cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T‐cell population and patient prognosis and reveal the development of irAEs in nivolumab‐treated patients. Thirty‐two patients were included in the study, and the mean follow‐up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD‐1 occupancy on eTregs and all‐cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD‐1 inhibitor therapy, implying that the inhibition of PD‐1/PD‐ligand 1 (PD‐L1) signaling on eTregs may attenuate antitumor effects.
Measurement of PD‐1 receptor occupancy. PBMCs were saturated with either unlabeled human IgG4 (isotype control) or nivolumab and then co‐stained with murine anti‐human IgG4 biotin plus streptavidin‐phycoerythrin.
The response rate to immune checkpoint inhibitors (ICIs) is approximately 10%-30% and only in a few cancer types. In the present study, we determined whether non-classical monocytes (NCMs) could ...enhance ICI efficacy in colon cancer using a syngeneic mouse model.
The MC38 C57BL/6 mouse colon cancer model was used. Cells collected from the bone marrow of C57BL/6 mice were cultured, and NCMs were fractionated by cell sorting and administered via the tail veins to the mice implanted with MC38 cells. The anti-mouse PD-L1 antibody was administered three times, and tumor volume and overall survival were observed.
More tumors were eradicated and more complete response occurred, after cotreatment with ICIs and NCMs than after treatment with ICIs alone. Moreover, no efficacy was observed when NCMs were administered alone.
NCMs enhance ICI efficacy. The underlying mechanisms and clinical applications will be studied in the future.
Background
Recently, intestinal bacteria have attracted attention as factors affecting the prognosis of patients with cancer. However, the intestinal microbiome is composed of several hundred types ...of bacteria, necessitating the development of an analytical method that can allow the use of this information as a highly accurate biomarker. In this study, we investigated whether the preoperative intestinal bacterial profile in patients with esophageal cancer who underwent surgery after preoperative chemotherapy could be used as a biomarker of postoperative recurrence of esophageal cancer.
Methods
We determined the gut microbiome of the patients using 16S rRNA metagenome sequencing, followed by statistical analysis. Simultaneously, we performed a machine learning analysis using a random forest model with hyperparameter tuning and compared the data obtained.
Results
Statistical and machine learning analyses revealed two common bacterial genera,
Butyricimonas
and
Actinomyces
, which were abundant in cases with recurrent esophageal cancer.
Butyricimonas
primarily produces butyrate, whereas
Actinomyces
are oral bacteria whose function in the gut is unknown.
Conclusion
Our results indicate that
Butyricimonas
spp. may be a biomarker of postoperative recurrence of esophageal cancer. Although the extent of the involvement of these bacteria in immune regulation remains unknown, future research should investigate their presence in other pathological conditions. Such research could potentially lead to a better understanding of the immunological impact of these bacteria on patients with cancer and their application as biomarkers.
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