Differential gene expression and tumormutanome analysis reveal significantly enriched pathways associated with higher tumor burden of M1 and M2 macrophages ::
Ravi Gupta, Nitin Mandloi, Ashwini Patil, Malini Manoharan, Rekha Sathian, Kiran Paul and Amitabha Chaudhuri
In the backdrop of the remarkable success checkpoint control inhibitors have shown in treating a variety of different cancers, this study focused on deeper assessment of the tumor and its microenvironment at the genetic and phenotypic level. Data from recent clinical trials have unequivocally established that the tumor microenvironment significantly impacts the efficacy of immune-oncology drugs.
The study which made a significant comparison between the tumor microenvironments of uveal melanoma vs skin cutaneous melanoma involved a gene expression signature-based approach to qualitatively and quantitatively assess the epithelial, stromal and immune content of tumors from RNA-seq data. These signatures were then applied singly, or in combination on the TCGA RNA-seq data from 33 cancers. As part of the study, 476 skin cutaneous melanoma (SKCM) and 80 melanoma (UVM) samples from TCGA were analysed.
The idea that gene expression signatures can address a critical unmet need in the immune-oncology space, which is to create a framework for treating tumors that carry less mutation burden combined with poor T-cell infiltration is well supported by the findings we obtained through this study.
Analysis of tumor microenvironment identifies pathways predicting response to checkpoint control inhibitors: A case study comparing the immune microenvironment of uveal melanoma vs skin cutaneous melanoma ::
Ashwini Patil, Nitin Mandloi, Rekha Sathian, Aparna Mohan, Malini Manoharan, Ravi Gupta and Amit Chaudhuri
With only a few studies having analyzed the interaction between granulocytic and monocytic myeloid derived suppressor cells in human cancers, MedGenome’s scientists have chosen to investigate their immune suppressive effect on the tumor microenvironment in this study. Clinical trials in the recent past have resulted in findings that strongly indicate a definite impact that the tumor microenvironment has on the efficacy of immuno-oncology drugs.
The study utilized OncoPeptTUME to identify tumors carrying different burdens of G-MDSCs and M-MDSCs from whole tumor RNA-seq data. Proprietary gene expression signatures were used, that discriminated G- from M- MDSCs on 9345 tumors from 33 cancers available in commonly used cancer genome databases. The analysis revealed that 28 of the 33 cancers have undetectable levels of G-MDSC, but exhibited high levels of M-MDSC cells. MedGenome’s findings support the understanding that granulocytic MDSCs are more prevalent in lymphoid organs and are not usually detected at a high level in tumor tissues.
OncoPeptTUME identifies tumor intrinsic and extrinsic factors promoting infiltration of granulocytic myeloid derived suppressor cells (G-MDSCs) in human cancers
Ravi Gupta, Kiran Paul, Nitin Mandloi, Malini Manoharan and Amit Chaudhuri
A critical phase in the development of cancer is the conversion of growth-suppressive normal tissue microenvironment into a growth-promoting tumor microenvironment. MedGenome conducted a study to interrogate the tumor epithelial and the stromal compartments in a cohort of tongue and buccal cancers, using NGS sequencing. With the help of DNA and RNA-seq data, the relative abundance of epithelial, stromal and immune cells and correlated these with the mutational burden of individual tumors was estimated. It was shown that the presence of driver mutations block immune cell infiltration in both buccal and tongue cancers. By contrast, smoking and use of alcohol sharply increased immune infiltration in buccal, but not in tongue cancers, suggesting that carcinogenic impact differentially affect the composition of the tumor stroma in these cancers.
Differential gene expression profile of tongue and buccal cancers produce unique and shared vaccine candidates for cancer immunotherapy ::
PapManoharan Malini, Iyer Laxman, Priyanka Shah, Kiran Paul, Amit Choudhary, Ravi Gupta
Large scale sequencing of cancer genomes have revealed several mutations that remain uncharacterized, of which only few mutations are tested for activating or loss of function. MedGenome conducted a study which utilized in-silico method to characterize 4096 mutations in 190 cancer census genes spread across 33 cancer groups. Mutations were studied to identify gain and loss of function mutations. The analysis revealed 2,614 destabilizing mutations which would relate to a loss of function in 185 genes and 433 stabilizing mutations in 125 genes which could have a gain of function role. The study showed that higher number of stabilizing mutations have been identified in TP53, CDKN2A and PIK3CA and destabilizing mutations are widely distributed across several genes.