Emer O'Connell1,2, Manuela Salvucci2, Ian S Reynolds1,2, Deborah A McNamara1,3, John P Burke1, Jochen H M Prehn4,5. 1. Department of Colorectal Surgery, Beaumont Hospital, Dublin 9, Ireland. 2. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 3. Department of Surgery, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 4. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. prehn@rcsi.ie. 5. Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland. prehn@rcsi.ie.
Abstract
BACKGROUND: Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC. METHODS: Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts. RESULTS: The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p < 0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p < 0.05), and mucinous status (B = 0.591; p < 0.01). CONCLUSION: Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.
BACKGROUND: Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC. METHODS: Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts. RESULTS: The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p < 0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p < 0.05), and mucinous status (B = 0.591; p < 0.01). CONCLUSION: Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.