scholarly journals Genotypic and phenotypic signatures to predict immune checkpoint blockade therapy response in patients with colorectal cancer

2018 ◽  
Vol 196 ◽  
pp. 62-70 ◽  
Author(s):  
Xianda Zhao ◽  
Audre May ◽  
Emil Lou ◽  
Subbaya Subramanian
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Therapy Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Comprehensive Molecular Characterization of Urachal Adenocarcinoma Reveals Commonalities With Colorectal Cancer, Including a Hypermutable Phenotype

2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jordan Kardos ◽  
Sara E. Wobker ◽  
Michael E. Woods ◽  
Matthew E. Nielsen ◽  
Angela B. Smith ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Transcriptome Profiling ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Rna Expression ◽  
Precision Oncology ◽  
Rare Type ◽  
Msh6 Mutation ◽  
Urachal Adenocarcinoma

Purpose Urachal adenocarcinoma is a rare type of primary bladder adenocarcinoma that comprises less than 1% of all bladder cancers. The low incidence of urachal adenocarcinomas does not allow for an evidence-based approach to therapy. Transcriptome profiling of urachal adenocarcinomas has not been previously reported. We hypothesized that an in-depth molecular understanding of urachal adenocarcinoma would uncover rational therapeutic strategies. Patients and Methods We performed targeted exon sequencing and global transcriptome profiling of 12 urachal tumors to generate a comprehensive molecular portrait of urachal adenocarcinoma. A single patient with an MSH6 mutation was treated with the anti–programmed death-ligand 1 antibody, atezolizumab. Results Urachal adenocarcinoma closely resembles colorectal cancer at the level of RNA expression, which extends previous observations that urachal tumors harbor genomic alterations that are found in colorectal adenocarcinoma. A subset of tumors was found to have alterations in genes that are associated with microsatellite instability ( MSH2 and MSH6) and hypermutation ( POLE). A patient with an MSH6 mutation was treated with immune checkpoint blockade, which resulted in stable disease. Conclusion Because clinical trials are next to impossible for patients with rare tumors, precision oncology may be an important adjunct for treatment decisions. Our findings demonstrate that urachal adenocarcinomas molecularly resemble colorectal adenocarcinomas at the level of RNA expression, are the first report, to our knowledge, of MSH2 and MSH6 mutations in this disease, and support the consideration of immune checkpoint blockade as a rational therapeutic treatment of this exceedingly rare tumor.

scholarly journals Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

2020 ◽  
Author(s):  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Lucia Montorsi ◽  
Amelia Acha-Sagredo ◽  
Lorena Benedetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Critical Threshold ◽  
Mutational Burden ◽  
Antigen Presenting

To dissect the determinants of the heterogeneous response of colorectal cancer (CRC) to immune checkpoint blockade, we profile tumour and immune infiltrates of 721 cancer regions from 29 patients treated with Pembrolizumab or Nivolumab. Combining multi-regional whole exome, RNA and T-cell receptor sequencing we show that anti-PD1 agents are most effective in CRCs with high mutational burden and low activation of the WNT pathway. However, above a critical threshold defining the hypermutated phenotype, response is no longer associated with mutational burden but rather with high clonality of immunogenic mutations, expanded T cells and active immune escape mechanisms. Using high-dimensional imaging mass cytometry and multiplexed immunofluorescence, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 infiltrates interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting their expansion in intra-tumour niches.

scholarly journals Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

2021 ◽  
Vol 118 (45) ◽  
pp. e2105323118
Author(s):  
William W. Ho ◽  
Igor L. Gomes-Santos ◽  
Shuichi Aoki ◽  
Meenal Datta ◽  
Kosuke Kawaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

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