bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer analysis of PBRM1 mutation and their association with immune-related biomarkers and prognosis.
Authors: He Xujun , Xin Yaqun , Yuan Hongling , Tao Houquan , Wang Qingqing , Zhu Honglin 
Published: June 2022

e14536 Background: Polybromo 1 ( PBRM1), which is required for the stability of the SWI/SNF chromatin remodeling complex, is often deleted or mutated in clear cell renal cell carcinoma (ccRCC). However, the prognostic value of PBRM1 in ccRCC with immunotherapy was controversial and less explored in other cancer types. Methods: The sequencing data and clinical information of patients were obtained from The Cancer Genome Atlas (TCGA) cohort (n = 10967) and the immunotherapy MSKCC cohort (n = 387). In TCGA cohort, the expression levels of PD1 were defined as high or low using a 75% cut-off. The association of PBRM1 mutation and related immune biomarkers such as PD1, TMB and immune infiltrates CD4+ and CD8+ T cells was analyzed. Results: Loss-of-function (LOF) of PBRM1 mutation ( PBRM1LOF), including frameshift, nonsense and splice, accounted for 61.4% of all somatic mutations, with a frequency of 2.2% across all cancer types. It is most common in renal clear cell carcinoma (KIRC; 23.2%, 119/512), followed by stomach adenocarcinoma (STAD; 4.1%, 18/440), uterine corpus endometrial carcinoma (UCEC; 3.8%, 20/529), and colon adenocarcinoma (COAD; 2.5%, 11/439) in TCGA cohort. In KIRC, no differences of PD1 expression (P = 0.307) and TMB (P = 0.389) were observed between patients with PBRM1LOF and non- PBRM1LOF mutations, while in STAD, UCEC and COAD, patients with PBRM1LOF mutations had significantly higher levels of PD1 (P = 0.002 in COAD, P < 0.001 in STAD and UCEC) and TMB (all P < 0.001). As for immune infiltrates, expression levels of CD4+ (P = 0.34) and CD8+ (P = 0.18) were found no difference between patients with PBRM1LOF and non- PBRM1LOF in KIRC. However, significantly higher expression levels of CD4+ (P = 0.0014) and CD8+ (P = 0.0016) in UCEC, and CD8+ in COAD (P = 0.04) were found in patients with PBRM1LOF compared with non- PBRM1LOF mutations. Further, in MSKCC cohort, a cohort of patients who had undergone immunotherapy, PBRM1LOF was shown no significant effect on patient outcome in KIRC (P = 0.42), while in other cancer types (COAD+STAD), PBRM1LOF trended towards a promising biomarker for better survival even though the difference was not statistically significant in this small cohort (P = 0.51). Conclusions: PBRM1LOF may play different prognostic roles on immunotherapy in different cancer types. In KIRC, PBRM1LOF was not associated with immune-related biomarkers as well as prognosis of immunotherapy. In COAD, STAD and UCEC, PBRM1LOF was positively associated with immune-related biomarkers and might be a promising biomarker for immunotherapy. This result needs further validation in a lager cohort.
Biodegradable nanoparticle-induced sting pathway activation for the treatment of cancer.
Authors: Podojil Joseph , Cogswell Andrew , Chiang Ming-Yi , Eaton Valerie , Efergan Igal , Neef Tobias , Xu Dan , Meghani Khyati , Yu Yanni , Orbach Sophia , Murthy Tushar , Boyne Michael , Elhofy Adam , Shea Lonnie , Meeks Joshua J. , Miller Stephen D. 
Published: June 2022

e14552 Background: Recent advances in the field of cancer immunology have highlighted the importance of the immune system for eliminating tumors. Numerous studies have shown that tumor-infiltrating immune cells such as antigen-presenting cells (APCs), T cells, and natural killer (NK) cells play critical roles in tumor control. However, the inflammatory anti-tumor immune response is counteracted by the induction of immune regulatory mechanisms within the tumor microenvironment (TME). These findings have led to the development of immune-targeted therapies, which are aimed at activating anti-tumor immune signaling pathways and enhancing anti-tumor immune function. While immunotherapies, have revolutionized the treatment of several solid tumors and leukemias, at best response rates remain low at 25%-30%, and a portion of patients eventually develop resistance to therapy leading to disease progression and mortality. Methods: We have previously reported the potent effects of 3-4 daily intravenous infusions of immune modifying poly(lactic- co-glycolic acid) (PLGA) nanoparticles, ONP-302, free from drugs or other bioactive agents, for the amelioration of acute inflammatory diseases by targeting myeloid cells. The present studies describe a novel use for ONP-302 nanoparticles, employing an altered dosing scheme to reprogram myeloid cells resulting in significant enhancement of tumor immunity. The efficacy of ONP-302 nanoparticles at inducing an anti-tumor immune response was evaluated using syngeneic mouse tumor models. Results: ONP-302 infusion decreased tumor growth via the activation of the cGAS/STING pathway within myeloid cells, and subsequently increased NK cell activation via an IL-15-dependent mechanism. Additionally, ONP-302 treatment increased PD-1/PD-L1 expression in the tumor microenvironment, thereby allowing for functionality of anti-PD-1 for treatment in the B16.F10 melanoma tumor model which is normally unresponsive to monotherapy with anti-PD-1. Conclusions: These findings indicate that ONP-302 allows for tumor control via reprogramming myeloid cells via activation of the STING/IL-15/NK cell mechanism, as well as increasing anti-PD-1 response rates.
Molecular classification for predicting the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer.
Authors: Hu Hailong , Niu Yuanjie , Wang HaiTao , Liu Huanhuan , Shen Chong , Da La , Zhao Gangjian , Wang Lili , Wu Zhouliang , Cao Shanbo , Lou Feng , Wang Huina 
Published: June 2022

e14563 Background: Bladder cancer is a molecularly diverse disease with heterogeneous clinical outcomes. Transcriptome-based molecular subtypes of muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) have been shown to be both prognostic and predictive. However, its predictive role in Chinese bladder cancer remains unclear. The aim of this study was to identify the predictive role of molecular subtypes in China bladder cancer with neoadjuvant therapy. Methods: The study was conducted from May 2020 to August 2021. Patients who were age 18 years or older, were diagnosed with NMIBC or MIBC, and neoadjuvant tislelizumab combining nab-paclitaxel followed by surgery were included. Multigenomic sequencing was performed. Molecular subtypes were identified by published consensus. Results: We prospectively recruited 30 patients for neoadjuvant tislelizumab combining nab-paclitaxel, including 14 patients with NMIBC and 16 patients with MIBC. For bladder cancer, 73.3% (22/33) patients responded to neoadjuvant tislelizumab combining nab-paclitaxel. In NMIBC groups, 64.3% (9/14) patients were pCR. The objective remission rate ( ORR) was 71.4%. 4 molecular classes were identified in Chinese NMIBC, including class 1 (7.1%), class 2a (35.7%), class 2b (50%), class 3 (7.1%). Interesting, ORR was significantly higher for patients with class 2b (5/7, 71.4%) as compared to class 2a (3/5,60%) before neoadjuvant. Molecular classes changed in 35.7% (5/14) of patients before and after neoadjuvant. After neoadjuvant, 80% of class 2b patients responded to neoadjuvant, and all class 2a patients did not respond to neoadjuvant. In MIBC groups, a pPR was achieved by 37.5% patients (6/16). The ORR was 75%. We found 4 molecular classes in Chinese MIBC: basal/squamous (43.8%), luminal unstable (25%), luminal papillary (25%), and stroma-rich (6.2%). Patients with basal/squamous (85.7%) and luminal unstable (75%) had significantly higher ORR than luminal papillary (50%) before neoadjuvant. Molecular classes changed in 44.4% (4/9) of patients before and after neoadjuvant. After neoadjuvant, all patients with stroma-rich responded to neoadjuvant. Conclusions: Molecular classification could predict the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer, which may be preferable when studying biomarkers of bladder cancer in the future.
The combination timing of radio-immunotherapy determines immune microenvironment remodeling and abscopal effect through eosinophils.
Authors: Zhu Xiaoxia , Li Shangbiao 
Published: June 2022

e14566 Background: Recently, several studies have confirmed the abscopal effect of tumor shrinkage outside the irradiated field induced by local radiotherapy (RT) combined with immunotherapy. The timing of the combination, including concurrent and sequential treatment, may affect the anti-tumor efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). However, the optimal timing of RT combined with immunotherapy to enhance the abscopal effect and the underlying mechanism are still unknown. Methods: The animal model of bilateral subcutaneous tumor of MC38 in C57BL/6J mice were randomly divided into four groups: PD-1 therapy (P1) group, radiotherapy (unilateral irradiation, 8Gy × 3F, the same below) concurrent with anti-PD-1 therapy (Con.) group, anti-PD-1 therapy one week after radiotherapy (Seq.1) group and anti-PD-1 therapy two weeks after radiotherapy (Seq.2) group. RNA sequencing was employed to identify differential genes. The changes of the immune microenvironment of tumor-draining lymph nodes (TDLN) and tumors were detected by flow cytometry. The expression of chemokine receptors, ligands, and cytokines was detected by qPCR, western blot, and ELISA. Results: The results showed that the survival benefit of sequential PD-1 inhibitor after RT was higher than that of the Con. group and P1 group., the survival benefited most in Seq.1 group, particularly. Similarly, tumor growth on both sides was significantly inhibited in Seq.1 group compared with the Con. group, P1 group, and Seq2. group. Furthermore, a combination of RT with anti-PD-1 inhibitor induced changes of immune microenvironment in irradiated tumor, abscopal tumor and TDLN. In the Seq.1 group, the tumor immune microenvironment was reshaped, including increased eosinophils and CD8+T cells infiltration, while decreased Treg, MDSCs, and TAMs frequency. Correspondingly, the expression of crucial chemokine receptors and ligands involved in chemotaxis of eosinophils and CTL CD8+T cells was up-regulated in tumors of mice in the Seq.1 group. After eosinophil neutralization in vivo, the survival of mice in Seq.1 group was significantly shortened. Besides, the anti-tumor effect and abscopal effect were significantly weakened, accompanied by deduction of the infiltration of T cells, especially cytotoxicity CD8+T cells in the immune microenvironment. Conclusions: Our results showed that RT combined with PD-1 inhibitors could induce a synergistic anti-tumor effect. Sequential PD-1 inhibitor one week after RT could enhance the anti-tumor effect most, including the abscopal effect. The mechanism related to eosinophils recruitment, which established a tumor-suppressive immune microenvironment mainly through enrichment of anticancer T lymphocytes in abscopal tumors. This study provides an insight for clinical precision treatment in combination of RT and immunotherapy.
The role and impact of immunotherapy in multiple malignancies in the Mexican population.
Authors: Juarez - Vignon Whaley Juan Jose , Sanchez Dominguez Gisela , Gonzalez Espinoza Iván Romarico , Garcia Montes Lizbett Vanessa , Alatorre-Alexander Jorge , Hernandez Flores Osvaldo , Garibay Diaz Julio Cesar , Rodriguez Cid Jeronimo Rafael Rafael 
Published: June 2022

e14570 Background: Cancer in Mexico represents the third cause of death nationally. Immunotherapy agents have changed management and prognosis of cancer patients. Immune-checkpoint agents are now being used as both first- and second-line treatment improving cancer patient prognosis, nevertheless it is not always accessible. Methods: Retrospective review of patients diagnosed with any type of cancer that received immunotherapy during their disease course from the last 5-years. We present the most common malignancies, immunotherapeutic regimens received, population characteristics and survival analysis. Results: 130 records of patients ≥18 years that received immunotherapy were included. 52.3% female with mean age of 59 years (range, 22-89 years), 48.5% former smokers (average pack/year of 22.5) and 31.5% asbestos exposure. 53.1% were ECOG 0 and 82.3% clinical stage IV. 62.3% of cases were lung adenocarcinoma, followed by lung epidermoid carcinoma (13.1%) and 10% small-cell lung carcinoma. Immunotherapeutic agents used included nivolumab in 63.1%, pembrolizumab 12.3%, nivolumab + ipilimumab 8.5%, durvalumab 6.2%, pembrolizumab + ipilimumab 4.6%. 36.2% of patients received immunotherapy as second line treatment, 30.0% as third and 23.8% as first line treatment. The best Response Evaluation Criteria in Solid Tumors (RECIST) was RECIST 3 in 46.2% followed by RECIST 0 with 25.4%. Median progression-free survival (PFS) was 5 months (95% CI; 3.883-6.117) and median OS of 13 months (95% CI; 10.210-15.790). Analysis per immunotherapy on PFS (p = 0.0414) and OS (p = 0.0046) demonstrated pembrolizumab had the longest median PFS with 19-months and OS with 22-months. Analysis between tumor types was significant for both PFS (p = 0.0018) and OS (p = 0.0090) with melanoma having the longest median PFS (42-months) and OS (46-months). Conclusions: Immunotherapy has changed cancer management; however, its use depends on specific biomarkers and adequate patient selection. Not all patients benefit from immunotherapy, in a country like ours where resources are limited, it is of vital importance to properly select candidates for immunotherapy. Even though, all patients had an FDA-approved indication at the time of receiving immunotherapy, PFS and OS are not as significant as Phase 3 studies demonstrate, this may be due to late stages, advanced ECOG, correct biomarkers availability and adequate patient selection. It is important to mention that about 40-60% of patients with immunotherapy do not respond adequately. In our study, because there is more evidence with pembrolizumab, the patients who received it were better chosen and therefore there was an impact in PFS and OS. Immunotherapy selection also depends on physician experience to the different immunotherapy regimens.
XIRP2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Chen Hualin , Liu Meilian , Luo Yiping , Zhao Lele , Huang Lingli , Xiao Mingzhe , Qi Chuang , Yang Zhixiong 
Published: June 2022

e14573 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Xin-actin binding repeat containing 2 (XIRP2) encodes an actin-cross-linking protein that was previously reported to be significantly mutated in breast cancer metastases. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between XIRP2 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between XIRP2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with XIRP2 mutation were significantly associated with better PFS (HR = 0.4; 95% CI, 0.21-0.75; P = 0.003) after ICIs therapy, compared with those with wide-type XIRP2. XIRP2 mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between XIRP2 mutation and PFS remained significant (HR = 0.4; 95% CI, 0.20-0.81; P = 0.011). In contrast, no association between XIRP2 mutation and OS (LUAD: P = 0.43 ; LUSC: P = 0.17) or PFS (LUAD: P = 0.54; LUSC: P = 0.19) was observed in TCGA datasets, suggesting that XIRP2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, XIRP2 mutation was significantly associated with higher M1 macrophage, CD8+ T cell, as well as lower Treg cell. Moreover, XIRP2 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that XIRP2 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of XIRP2 in immunotherapy is needed to be further studied.
PD1 inhibition effect on immunization with MRNA vaccines against SARS-CoV-2.
Authors: Majer Martin , Knoefler Justin , Little Elizabeth Fauchier , Powell Megan , Ordorica Edward J. , Arakozie Roxanna , Tran Phuc , Ha Duke , Cheam Socheat , Lay Linda , Le Andrew , Park Min , Atwal Gurbir , Nguyen Hanh , Yang Mee , Ghuman Sudeep Kaur , Jones Sarah , Singh Narinder , Shannon Roy 
Published: June 2022

e14594 Background: We provide care for the rural, low-income, and underserved population of Oroville. The community has a vaccination rate of 50% and booster rate of over 20% in the 3rd year of the ongoing global SARS-CoV-2 pandemic in 2022. During this period, a subset of our cancer patients benefited from the use of immune checkpoint inhibitors. Methods: This is a cross-sectional observational study of the effectiveness of a mRNA-based vaccine in medical care workers compared to patients with systemic malignancies treated with immunomodulation of PD-1 and CTLA-4 inhibitors. The study was approved by the hospital IRB. We evaluated the total anti-Spike protein antibody titer using a commercial semi-quantitative assay, Labcorp Test #164090. All subjects received 3 doses of the mRNA vaccine. We excluded anyone who was administered therapeutic monoclonal antibodies (mAb) or had a recent infection within 120 days. Results: Subjects with systemic malignancies were significantly older, p = 0.0001 by t-test: median age: 76, range: 64-82, compared to health care workers: median age: 52, range: 21-75. Accrual had to be prematurely stopped upon the arrival of Omicron wave in the community. Out of the seven subjects treated with immunomodulation, six received nivolumab, including two in combination with ipilimumab. One subject received pembrolizumab. Six of the subjects had metastatic disease: one was treated adjuvantly for locally advanced esophageal adenocarcinoma. The rest had NSCLC and one case of urothelioma. We divided the groups to those who had the highest titer of antibody versus everybody else and found a similar distribution in both groups using the Chi2 test. The vast majority of the healthcare workers, 24/27 or 89%, had above the upper limit antibody titer. Patients with systemic malignancy, 5/7 or 71%, had above the upper limit antibody titer p = N.S. Conclusions: Three doses of the mRNA vaccine provided high titers irrespective of frailty or age. We hypothesize that immunomodulation could favorably affect vaccination response.
Association of opioid use with response to immune checkpoint inhibitors.
Authors: Weinfeld Michael , Wang Heidy , Liu Li C. , Pasquinelli Mary , Huber Michael , Feldman Lawrence Eric , Weinberg Frank 
Published: June 2022

e14595 Background: Management of cancer-related pain with opioids is hypothesized to decrease efficacy of immune checkpoint inhibitors (ICIs) through immunosuppressive effects of opioids, such as down-regulation of major histocompatibility complex class II. There is limited evidence on how opioids affect outcomes in patients receiving ICIs. Methods: We identified 212 patients at the University of Illinois Hospital and Health Sciences System who received an ICI between January 1, 2015 and July 31, 2021. Overall survival (OS) and progression-free survival (PFS) were compared in patients who were not treated with opioids, patients treated with low-dose opioids (defined as less than 60 morphine milliequivalents per day), and patients treated with high-dose opioids (defined as at least 60 morphine milliequivalents per day). Results: Out of 212 patients who received an ICI, 98 (46.2%) received no opioids, 69 (32.6%) received low-dose opioids, and 45 (21.2%) received high-dose opioids. Among all patients, 105 (49.5%) died during the study duration. The overall median survival time was 23 (95% CI = 16, 38) months for the entire sample. Patients who received opioids at any dose had a median OS of 17 months compared to 37 months in those who received no opioids (HR = 1.53, p = 0.0385). When patients receiving opioids were further divided by dose, survival time was highest in those receiving no opioids, next highest in those receiving low-dose opioids, and lowest in those receiving high-dose opioids (37 months vs 18 months vs 10 months, p = 0.0515). Among all 212 patients, progression of disease occurred in 84 (39.6%) patients. The overall median time-to-progression was 24 months. There was no significant difference in median PFS between those treated with opioids (36 months) versus not (23 months, p = 0.156). Conclusions: We observed an association between opioid therapy, especially at higher doses, and decreased median OS in patients receiving ICIs. On the other hand, there was no statistical association between opioid therapy and median PFS. These data highlight a potential drug interaction in oncology care, and further analysis looking at duration of opioid use and ECOG PS is planned.[Table: see text]