Research
Rectal cancer is one of the ten most common cancers worldwide, contributing to nearly 0.5 million cancer-related deaths in 2018. Despite recent advances in the treatment of cancer patients, surgical resection with curative intent is still considered the most common approach for the treatment of rectal cancer. This approach often requires extensive surgery, which has a massive impact on the quality of life of rectal cancer patients. Apart from surgery, management of rectal cancer patients largely relies on conventional methods such as chemotherapy and radiotherapy. Remarkably, only 16% of the patients receiving chemotherapy and/or radiotherapy reach pathological complete response. A major obstacle in the development of effective therapies lays on the intrinsic and extrinsic biological heterogeneity of these tumors. Our lab focuses on studying the tumor immune microenvironment in rectal cancer with the aim to uncovering ways to harness it for therapy.
Capturing cellular dynamics in rectal cancer using scRNA sequencing
For decades, rectal cancer has been considered as a single entity together with colon cancer, referred to as colorectal cancer. However, it appears increasingly clear that these tumors are distinct. Whilst extensive bulk DNA and RNA analysis enabled the classification of patients according to their molecular profile, the clinical and therapeutic benefit of these classifications is rather poor. Further characterization of the rectal cancer microenvironment using single-cell transcriptome analysis has the potential to offer a deeper understanding of its cellular components and dynamic interactions during therapy, which may ultimately improve patient stratification and treatment responses. Therefore, our study aims at bridging this knowledge gap by generating a single-cell atlas of RC tumor cells and their surrounding immune and stromal cells, as well as exploring cell-specific transcriptional changes related to specific therapeutic interventions.
scRNA sequencing of a rectal cancer specimen
Tackling immune exclusion in microsatellite stable rectal cancer
Reshaping the tumor microenvironment is a key strategy to improve the treatment of human cancers, as highlighted by successes in immune checkpoint blockade. Notably, responsiveness to these novel treatments is often associated with the presence of a local T cell-inflamed tumor microenvironment. Most solid tumors, however, do not show evidence of T cell infiltration. These tumors are notoriously refractory to immunotherapies and microsatellite stable rectal cancer falls into this category. By applying a combination of in vitro and in vivo rectal cancer models, ‘omics’ approaches and advanced imaging techniques, we aim at developing alternative approaches to promote de novo T cell activation and infiltration into the tumor microenvironment of microsatellite stable rectal cancer and other non-inflamed tumors.
Primary organoid - T cell co-culture
Breaking barrier to successfully treat rectal cancer - a clinical trial
Despite recent successes in immunotherapy, the clinical benefits of immune checkpoint inhibitors are usually limited to a subset of cancer patients. In colorectal cancer, patients with mismatch repair deficiency or high microsatellite instability derive benefit from these treatments. On the other hand, immune checkpoint inhibitors have not shown meaningful activity in microsatellite stable colorectal cancer which represent 85% of all colorectal cancers. Failure in achieving durable responses is often associated with scarce or absent T cell infiltration, indicative of an “immune-desert/cold” tumor microenvironment. In order to broaden the application of immune checkpoint inhibitors to microsatellite stable rectal cancers, novel therapeutic approaches aiming at reconditioning the tumor microenvironment by either promoting T cell activation and infiltration are required. Our clinical trial (PEMREC) is the first study evaluating a novel therapeutic approach that combines radiotherapy with the anti-PD1 antibody. This study could lead to a major breakthrough in the treatment of rectal cancer.
Representative description of the rectal cancer microenvironment after radio-immunotherapy
Explore functional states and spatial interactions between cell types using multiplexed-IF and advanced image analysis
The tumor microenvironment is a complex network of interactions between cellular and extracellular components. Organization of these components modulate cell behaviours, which ultimately shape tumor evolution and effectiveness of anti-tumor treatments. It is increasingly recognized that a deep characterization of the tumor microenvironment is required for the identification of novel prognostic and predictive biomarkers. Here, we aim at applying a multiplexed immunofluorescent technology to FFPE tissue along with a software for digital pathology to characterize the tumor microenvironment of rectal cancer.
Multiplex-IF of a rectal cancer specimen. Courtesy of Mario Kreuztfeldt