scholarly journals Genomic investigation of co-targeting tumor immune microenvironment and immune checkpoints in pan-cancer immunotherapy

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Xing Huang ◽  
Tianyu Tang ◽  
Gang Zhang ◽  
Zhengtao Hong ◽  
Jian Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Immunotherapy ◽  
Critical Role ◽  
Prognostic Significance ◽  
Time Factors ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Cancer Type ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

AbstractDrugs that target immune checkpoints (ICPs) have become the most popular weapons in cancer immunotherapy; however, they are only beneficial for a small fraction of patients. Accumulating evidence suggests that the tumor immune microenvironment (TIME) plays a critical role in anti-cancer immunity. This study aimed to assess the potential merits and feasibility of combinational targeting ICPs and TIME in cancer immunotherapy. A total of 31 cancer type-specific datasets in TCGA were individually collected by the publicly available web servers for multiple bioinformatic analyses of ICPs and TIME factors. GEPIA was used to calculate the prognostic indexes, STRING was used to construct protein–protein interactions, cBioPortal was used for visualization and comparison of genetic alterations, and TISIDB was used to explore the correlation to tumor-infiltrating lymphocytes (TILs). Intriguingly, TIME factors were identified to have more global coverage and prognostic significance across multiple cancer types compared with ICPs, thus offering more general targetability in clinical therapy. Moreover, TIME factors showed interactive potential with ICPs, and genomic alteration of TIME factors coupled with that of ICPs, at least in pancreatic cancer. Furthermore, TIME factors were found to be significantly associated with TILs, including but not limited to pancreatic cancer. Finally, the clinical significance and translational potential of further combination therapies that incorporate both ICP inhibitors and TIME factor-targeted treatments were discussed. Together, TIME factors are promising immunotherapeutic targets, and a combination strategy of TIME factors-targeted therapies with ICP inhibitors may benefit more cancer patients in the future.

scholarly journals Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tianyu Tang ◽  
Xing Huang ◽  
Gang Zhang ◽  
Zhengtao Hong ◽  
Xueli Bai ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Great Success ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Cancer Immunotherapeutic

AbstractDespite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.

scholarly journals Combinational blockade of MET and PD-L1 improves pancreatic cancer immunotherapeutic efficacy

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Enliang Li ◽  
Xing Huang ◽  
Gang Zhang ◽  
Tingbo Liang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Immunotherapy ◽  
Tyrosine Kinases ◽  
Prognostic Significance ◽  
Immunohistochemical Analysis ◽  
Immune Checkpoint Blockade ◽  
Pancreatic Tumors ◽  
Immune Checkpoints ◽  
Pancreatic Cancers

Abstract Background Dysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy. Methods Kaplan–Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune “hot” and “cold” pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Two in vivo models bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy. Results MET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune “hot” and “cold” pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer. Conclusions This study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.

scholarly journals Alteration in the immune microenvironment based on APC status in MSS/pMMR colon cancer data retrieved from TCGA

2020 ◽  
Author(s):  
Haishan Lin ◽  
Hongchao Zhen ◽  
Kun Shan ◽  
Xiaoting Ma ◽  
Bangwei Cao
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Enrichment Analysis ◽  
Tumor Immunotherapy ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Cancer Data ◽  
T Cell Infiltration ◽  
Colon Cancers ◽  
Tumor Immune Microenvironment

Abstract Immunotherapy is currently the most advanced anti-tumor treatment approach. The efficacy of anti-tumor immunotherapy is closely related to the tumor immune microenvironment, including immune cells, infiltration of immune factors, and expression of immune checkpoints. At present, the biomarkers for predicting the efficacy of colon cancer immunotherapy do not cover all colon cancer patients suitable for immunotherapy. In this study, TCGA database was used to identify tumor genotypes suitable for anti-tumor immunotherapy. We found that some of the MSS/pMMR populations, that were initially considered unsuitable for immunotherapy, might actually be suitable. In APC-wt/MSS colon cancer, the expression of PD-1, PD-L1, CTLA4 and CYT（GZMA and PRF1）were increased. Based on calculations done by ESTIMATE and CIBERSORT algorithms, the ImmunoScore and the proportion of CT8+ T cell infiltration is increased in these patients. Enrichment analysis was done to screen signaling pathways involved in immune response, extracellular matrix, and cell adhesion. Tumors from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Based on the results, we found that some colon cancers of APC-wt/MSS are classified by Tumor Immune Microenvironment types (TIMTs) TMIT I. So that we speculate that APC-wt/MSS colon cancer patients could benefit from anti-tumor immunotherapy.

scholarly journals Clinical Verification of Body Mass Index and Tumor Immune Response in Patients With Breast Cancer Receiving Preoperative Chemotherapy

2021 ◽  
Author(s):  
Koji Takada ◽  
Shinichiro Kashiwagi ◽  
Yuka Asano ◽  
Wataru Goto ◽  
Rika Kouhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Mass Index ◽  
Body Mass ◽  
Preoperative Chemotherapy ◽  
Early Stage ◽  
Normal Weight ◽  
World Health ◽  
Cancer Type ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

Abstract PurposeThe body mass index (BMI) is commonly used as a simple indicator of obesity; patients with early-stage breast cancer who are obese (OB) per BMI measurements have been shown to have high postoperative recurrence and low survival rates. On the other hand, it has been shown that lymphocytes present in the vicinity of malignant growths that are involved in the tumors’ immune responses influence the efficacy chemotherapy. Therefore, we hypothesized that OB patients with breast cancer have a lower density of tumor-infiltrating lymphocytes (TILs), which may influence the therapeutic effect of preoperative chemotherapy (POC). In this study, we measured pretreatment BMI and TILs in patients with breast cancer who underwent POC, examined the correlations between these two factors, and retrospectively analyzed their therapeutic outcomes and prognoses.MethodsThe participants in this study were 421 patients with breast cancer who underwent surgical treatment after POC between February 2007 and January 2019. The patient’s height and weight were measured before POC to calculate the BMI (weight [kg] divided by the square of the height [m2]). According to the World Health Organization categorization, patients who weighed under 18.5 kg/m2 were classified as underweight (UW), those ≥18.5 kg/m2 and >25 kg/m2 were considered normal weight (NW), those ≥25 kg/m2 and <30 kg/m2 were overweight (OW), and those ≥30 kg/m2 were OB. The TILs were those lymphocytes that infiltrated the tumor stroma according to the definition of the International TILs Working Group 2014.ResultsThe median BMI was 21.9 kg/m2 (range, 14.3–38.5 kg/m2); most patients (244; 64.5%) were NW. Among all 378 patients with breast cancer, the TIL density was significantly lower in OB than in NW and OW patients (vs. NW: p=0.001; vs. OW: p=0.003). Furthermore, when examining patients with each breast cancer type individually, the OS of those with TNBC who had low BMIs was significantly poorer than that of their high-BMI counterparts (log rank p=0.031).ConclusionsOur data did not support the hypothesis that obesity affects the tumor immune microenvironment; however, we showed that being UW does affect the tumor immune microenvironment.

scholarly journals M1 Macrophage and M1/M2 ratio defined by transcriptomic signatures resemble only part of their conventional clinical characteristics in breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Masanori Oshi ◽  
Yoshihisa Tokumaru ◽  
Mariko Asaoka ◽  
Li Yan ◽  
Vikas Satyananda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Biology ◽  
Clinical Characteristics ◽  
Critical Role ◽  
Immune Microenvironment ◽  
Gene Sets ◽  
M1 Macrophage ◽  
Tumor Immune Microenvironment ◽  
Cell Cycle Related Gene ◽  
High Level

Abstract Tumor associated macrophages (TAMs) play a critical role in biology of various cancers, including breast cancer. In the current study, we defined “M1” macrophage and “M1”/“M2” ratio by transcriptomic signatures using xCell. We investigated the association between high level of “M1” macrophage or “M1”/“M2” ratio and the tumor immune microenvironment by analyzing the transcriptome of publicly available cohorts, TCGA and METABRIC. We found that “M1” high tumors were not associated with prolonged survival compared with “M1” low tumors, or with the response to neoadjuvant chemotherapy. “M1” high tumors were associated with clinically aggressive features and “M1” high tumors enriched the cell proliferation and cell cycle related gene sets in GSEA. At the same time, “M1” high tumors were associated with high immune activity and favorable tumor immune microenvironment, as well as high expression of immune check point molecules. Strikingly, all these results were mirrored in “M1”/“M2” ratio high tumors. In conclusion, transcriptomically defined “M1” or “M1”/“M2” high tumors were associated with aggressive cancer biology and favorable tumor immune microenvironment but not with survival benefit, which resembled only part of their conventional clinical characteristics.

scholarly journals The Immune Microenvironment in Pancreatic Cancer

2020 ◽  
Vol 21 (19) ◽  
pp. 7307 ◽  
Author(s):  
Magdalena Huber ◽  
Corinna U. Brehm ◽  
Thomas M. Gress ◽  
Malte Buchholz ◽  
Bilal Alashkar Alhamwe ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Cellular Interactions ◽  
Therapeutic Approaches ◽  
Immune Microenvironment ◽  
Cellular Immune

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

scholarly journals From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 309 ◽  
Author(s):  
Chiara Bazzichetto ◽  
Fabiana Conciatori ◽  
Claudio Luchini ◽  
Francesca Simionato ◽  
Raffaela Santoro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Myeloid Cells ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Precision Oncology ◽  
Cancer Type ◽  
Tumor Type ◽  
Driver Genes

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies

scholarly journals Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

2018 ◽  
Vol 24 (32) ◽  
pp. 3583-3616 ◽  
Author(s):  
Daniela Cornelia Lazăr ◽  
Mihaela Flavia Avram ◽  
Ioan Romoșan ◽  
Mărioara Cornianu ◽  
Sorina Tăban ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Prognostic Significance ◽  
Future Perspectives ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment
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