Scientists uncover ways on how cancers can escape the immune system

June 6, 2017

A team of Singapore scientists has discovered new insights on how cancers evade the immune system. Using gastric cancer (GC), the third leading cause of cancer death worldwide, the conclusion made may be applicable to other major cancers with potential implications, that cancers might be better treated with immunotherapy, one of today’s most promising classes of anti-cancer drugs.

Promoters are regions in the genome that regulate the expression of genes, similar to the switch of a light bulb. Using an ultra-sensitive technique called NanoChIP-seq, the team surveyed the promoter landscape for GC to better understand the epigenetic mechanisms contributing to GC development. The team found that in GCs, gene promoters are dysregulated in a way that alters a tumour’s antigenic profile to evade the body’s immune system.

The study involved scientists and clinicians from Duke-NUS Medical School in the US, Genome Institute of Singapore, Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), and National Cancer Centre Singapore (NCCS).

“Using the NanoChIP-seq platform invented in Singapore, we created comprehensive epigenetic profiles for both GC and normal tissues,” explained team leader Professor Patrick Tan. “Epigenetics is a process by which a cell’s DNA is chemically modified by the environment, to change gene expression. By comparing the epigenetic profiles of gastric tumors to normal tissues from the same patient, we were able to identify those promoters specifically altered in GC tissues.” Professor Tan is a Faculty Member of Duke-NUS Medical School, Deputy Executive Director of the Biomedical Research Council at the Agency for Science, Technology and Research (A*STAR), and also Senior Principal Investigator at CSI Singapore and Principal Investigator at NCCS.

Just like how a light can be controlled by multiple switches to influence its intensity and color, the team identified hundreds of genes controlled by multiple promoters, causing alternate versions of that gene to be produced. The team demonstrated that some of these gene variants are capable of stimulating cancer growth. Strikingly, the team also found that many of these alternate gene variants produced in gastric tumors were also less likely to stimulate the immune system compared with their normal counterparts.

“Our data, combining computational, experimental assays, and analyses of human gastric cancers, indicates that the use of these less immunogenic variants may enhance the ability of a tumor to bypass the host’s immune system. This process is referred to as tumor immunoediting,” added Aditi Qamra, graduate student at the Genome Institute of Singapore and first author of this study. She is also a graduate student with the Department of Physiology at the NUS Yong Loo Lin School of Medicine.

The findings provide important insights into mechanisms used in cancer development and may have implications for cancer immunotherapy. While striking clinical responses have been seen in some patients treated with immunotherapy, these drugs are expensive, associated with side effects, and not all patients respond to the treatment.

The team’s results suggest that studying the promoter profiles of tumors may possibly identify those patients who would be responsive to immunotherapy. Moreover, the team also identified cellular pathways required by the tumor cell to maintain expression of the less immunogenic gene variants. The team is now exploring if targeting these pathways, combined with immunotherapy, can increase the proportion of patients that might respond to such drugs.

The team’s research was performed as part of the Singapore Gastric Cancer Consortium, supported by the A*STAR, Duke-NUS Medical School, as well as the National Research Foundation Singapore under its Translational and Clinical Research Flagship Programme (NMRC/TCR/009-NUHS/2013) administered by the Singapore Ministry of Health’s National Medical Research Council. The team is also working with ETPL, the commercialization arm of A*STAR, to develop the Nano-ChIPseq platform into a start-up, so that the platform is made available to more academic and industry customers.

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