Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Liming Gui ◽  
◽  
Zhixue Wang ◽  
Pan Yin ◽  
Bin Ma ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Costimulatory Molecules ◽  
Mouse Tumor ◽  
Antitumor Effects ◽  
Immune Effector ◽  
Lung Cancers ◽  
Tnf Superfamily

Cancer immunotherapy has emerged as a promising treatment that utilizes the innate or adaptive immunity to generate a robust killing of malignant cells. However, only a limited number of cancer patients showed responsiveness to immunotherapies such as checkpoint inhibitors, suggesting the need for potent alternative strategies. In the present study, we explored the therapeutic potentials of costimulatory molecules including TNF superfamily member 4 (TNFSF4), member 9 (TNFSF9), and member 18 (TNFSF18). In tumor samples from human colorectal and lung cancer patients, expression of these factors positively correlated with lymphocyte infiltration and expression of several immune effector genes. In syngeneic mouse tumor models, overexpression of the TNF superfamily costimulatory factors in murine colorectal or lung cancer cells significantly suppressed tumor progression. Especially, TNFSF9 and 18 showed stronger antitumor effects than TNFSF4. Together, our study demonstrated the great potential of cancer immunotherapy targeting these immune costimulatory molecules.

Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors

Science ◽  
2017 ◽  
Vol 359 (6371) ◽  
pp. 91-97 ◽  
Author(s):  
Bertrand Routy ◽  
Emmanuelle Le Chatelier ◽  
Lisa Derosa ◽  
Connie P. M. Duong ◽  
Maryam Tidjani Alou ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Gut Microbiome ◽  
Fecal Microbiota Transplantation ◽  
Checkpoint Inhibitors ◽  
Interleukin 12 ◽  
Mouse Tumor ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Primary Resistance ◽  
Clinical Responses

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance ofAkkermansia muciniphila. Oral supplementation withA. muciniphilaafter FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+T lymphocytes into mouse tumor beds.

Radiation therapy and immune-related side effects in patients treated with PD-1 inhibitors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 207-207
Author(s):  
Nadine Abdallah ◽  
Suketu Nagin Patel ◽  
Misako Nagasaka ◽  
Seongho Kim ◽  
Harold E. Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Side Effects ◽  
Cancer Patients ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Lung Cancer Patients ◽  
Immune Mediated ◽  
Increased Risk ◽  
Thoracic Radiation

207 Background: Checkpoint inhibitors exert their antitumor effects by producing a heightened immune state, and inadvertently give rise to immune-mediated toxicities, including pneumonitis and hypothyroidism. We investigated whether these side effects were more common in patients who were treated with both PD-1 inhibitors and radiation. Methods: Our institution’s pharmacy database was used to collect data on patients who received ≥ 1 dose of PD-1 inhibitors, with or without radiation before August 31, 2016. Adverse effects of hypothyroidism, and pneumonitis were recorded and graded based on CTCAEv4. A logistic regression analysis was performed between radiation and hypothyroidism among patients with Hodgkin’s lymphoma (HL) and head and neck squamous cell carcinoma (HNSCC) and between radiation therapy (RT) and pneumonitis in lung cancer patients. Results: 231 patients received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92). There were 125 patients (54%) with lung cancer, 18 (8%) with HL and 9 (4%) with HNSCC. 115 patients received radiation. HL and HNSCC patients had higher odds to experience hypothyroidism (adjusted p = 0.023) but this did not seem to be due to RT exposure [HR:0.156, 95% CI 0.008-1.122, p = 0.110]. Lung cancer patients with thoracic radiation had higher odds to experience pneumonitis [HR:2.206, 95% CI 0.451-15.931] although this was not statistically significant (p = 0.358). Conclusions: There was no association between RT and hypothyroidism. Our results suggested a possible increased risk of pneumonitis with thoracic radiation among lung cancer patients treated with PD-1 inhibitors, although statistically insignificant. Larger prospective studies are needed to further delineate this effect.

scholarly journals Circulating regulatory T cells predict efficacy and atypical responses in lung cancer patients treated with PD-1/PD-L1 inhibitors

2021 ◽  
Author(s):  
Da Hyun Kang ◽  
Chaeuk Chung ◽  
Pureum Sun ◽  
Da Hye Lee ◽  
Song-I Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Advanced Nsclc ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Treg Cells ◽  
University Hospital ◽  
X Rays ◽  
Lung Cancer Patients ◽  
National University

Abstract Background Immune checkpoint inhibitors (ICIs) have become the standard of care for a variety of cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the frequency of pseudoprogression and hyperprogression in lung cancer patients treated with ICIs in the real world and aimed to discover a novel candidate marker to distinguish pseudoprogression from hyperprogression soon after ICI treatment. Methods This study included 74 patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors at Chungnam National University Hospital (CNUH) between January 2018 and August 2020. Chest X-rays were examined on day 7 after the first ICI dose to identify changes in the primary mass, and the response was assessed by computed tomography (CT). We evaluated circulating regulatory T (Treg) cells using flow cytometry and correlated the findings with clinical outcomes. Results The incidence of pseudoprogression was 13.5%, and that of hyperprogression was 8.1%. On day 7 after initiation of treatment, the frequency of CD4+CD25+CD127loFoxP3+ Treg cells was significantly decreased compared with baseline (P = 0.038) in patients who experienced pseudoprogression and significantly increased compared with baseline (P = 0.024) in patients who experienced hyperprogression. In the responder group, the frequencies of CD4+CD25+CD127loFoxP3+ Treg cells and PD-1+CD4+CD25+CD127loFoxP3+ Treg cells were significantly decreased 7 days after commencement of treatment compared with baseline (P = 0.034 and P < 0.001, respectively). Conclusion Circulating Treg cells represent a promising potential dynamic biomarker to predict efficacy and differentiate atypical responses, including pseudoprogression and hyperprogression, after immunotherapy in patients with NSCLC.

scholarly journals Higher CD4/CD8 ratio of pleural effusion predicts better survival for lung cancer patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Po-Hsin Lee ◽  
Tsung-Ying Yang ◽  
Kun-Chieh Chen ◽  
Yen-Hsiang Huang ◽  
Jeng-Sen Tseng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pleural Effusion ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Lung Cancer Patients ◽  
Predicting Factor ◽  
Type 3

AbstractPleural effusion is a rare immune-related adverse event for lung cancer patients receiving immune checkpoint inhibitors (ICIs). We enrolled 281 lung cancer patients treated with ICIs and 17 were analyzed. We categorized the formation of pleural effusion into 3 patterns: type 1, rapid and massive; type 2, slow and indolent; and type 3, with disease progression. CD4/CD8 ratio of 1.93 was selected as the cutoff threshold to predict survival. Most patients of types 1 and 2 effusions possessed pleural effusion with CD4/CD8 ratios ≥ 1.93. The median OS time in type 1, 2, and 3 patients were not reached, 24.8, and 2.6 months, respectively. The median PFS time in type 1, 2, and 3 patients were 35.5, 30.2, and 1.4 months, respectively. The median OS for the group with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were not reached and 2.6 months. The median PFS of those with pleural effusion CD4/CD8 ≥ 1.93 and < 1.93 were 18.4 and 1.2 months. In conclusion, patients with type 1 and 2 effusion patterns had better survival than those with type 3. Type 1 might be interpreted as pseudoprogression of malignant pleural effusion. CD4/CD8 ratio ≥ 1.93 in pleural effusion is a good predicting factor for PFS.

scholarly journals Soluble c-Met Is a Reliable and Sensitive Marker to Detect c-Met Expression Level in Lung Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huilai Lv ◽  
Baoen Shan ◽  
Ziqiang Tian ◽  
Yong Li ◽  
Yuefeng Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Tissue Sample ◽  
Sample Collection ◽  
Lung Cancers ◽  
Lung Cancer Patients ◽  
Lung Cancer Therapy ◽  
Reliable Marker ◽  
Soluble C ◽  
Sensitive Marker

c-Met has been demonstrated as an attractive target in lung cancer therapy. Current studies showed that detection of c-Met status in tumor is critical in Met-targeted therapy. However not all patients are suitable for tissue sample collection. It is important to discover novel surrogate markers to detect c-Met status. In the study, soluble c-Met (s-Met) in plasma from 146 Chinese lung cancer patients and 40 disease-free volunteers was measured by enzyme-linked immunosorbent. In parallel, expression of c-Met in those tumors was also assessed by immunohistochemistry. Results showed that, in 146 lung cancer patients, 93 were c-Met expression positive and 74 of 93 were overexpressed. In c-Met-overexpressed patients, plasma s-Met was significantly increased. And further studies showed that plasma s-Met linearly correlated with c-Met expression in tumor. After tumor was removed in Met-overexpressed patients via resection, plasma s-Met significantly decreased to basal level. In addition, plasma s-Met showed to be poorly correlated with tumor size in Met-overexpressed patients. These results demonstrated that plasma s-Met is a sensitive and reliable marker to detect c-Met overexpression in lung cancers, and it is independent of tumor volume.

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