Abstract 499P
Background
MSI status in metastatic colorectal cancer (mCRC) is associated with benefit from immune checkpoint inhibitors (ICI). However, this biomarker needs to be refined towards a better patient selection. Other biomarkers besides MSI have been explored, including high PD-L1 expression in tumor cells or tumor infiltrating immune cells, high prevalence of tumor-infiltrating lymphocytes and B cells, IFN-g signatures and high tumor mutational burden. Here we explore the immune cell landscape and inflamed biomarkers in MSS and MSI primary colorectal tumors and metastatic lesions.
Methods
We downloaded The Cancer Genome Atlas colorectal RNA-seq data (RPKM) and MSI status from cBioportal (Cerami et al 2012). The abundance of 64 distinct immune or stromal cell types was inferred through xCell (Aran et al 2017). xCell outperforms methods to portrait tumoral cell infiltration by learning from the expression profiles of thousands of pure cell types and validating the signatures through in-silico simulations and flow cytometry phenotyping. IFN-g signature (6 genes) was calculated as specified in Ayers et al 2017.
Results
MSI colorectal tumors tended to present high expression of PD-L1, an IFN-g signature and CD8+ Tcell infiltration, in contrast to MSS cases (p < 0.001). However, CD8+Tcell infiltration and high levels of IFN-g signature were not constant in MSI tumors, while some MSS tumors presented an IFN-g signature and high PD-L1 expression. Interestingly, some MSI tumors showed high presence of myeloid cells (p < 0.001) and B cells were present in the tumors presenting high levels of CD8 T cell infiltration but also in some MSS tumors with low CD8 T cell infiltration. An important group of MSS tumors showed high infiltration on NK cells (p < 0.001). Presence of endothelial cells was independent of microsatellite status, although there was an increased presence of fibroblasts in the MSS tumors (p = 0.012).
Conclusions
MSI status is not an optimal biomarker to classify inflamed mCRC. These tumors present a complex inmune-biology which includes multiple immune-phenotypes that could be responsible for the diversity on immune-responses in MSI and MSS mCRC. The implementation of multiomic approach is necessary to improve clinical efficacy of cancer inmunotherapy in mCRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
I. Baraibar Argota: Honoraria (self): Sanofi; Travel/Accommodation/Expenses: Amgen. G. Argiles Martinez: Advisory/Consultancy: Roche, Bristol-Myers Squibb, ; Advisory/Consultancy: Genentech/Roche, ; Advisory/Consultancy: Bayer; Advisory/Consultancy: Servier; Travel/Accommodation/Expenses: Bayer; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Servier. F.J. Ros Montañá: Honoraria (self): Sanofi; Travel/Accommodation/Expenses: Amgen. J.L. Cuadra Urteaga: Advisory/Consultancy, Travel/Accommodation/Expenses: Hoffman La-Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Advisory/Consultancy, Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi. J. Tabernero: Advisory/Consultancy: Array Biopharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Chugai; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Advisory/Consultancy: Molecular Part; Advisory/Consultancy: Genentech, Inc.; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Genmab A/S; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: Menarini; Advisory/Consultancy: MSD; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene Limited; Advisory/Consultancy: Inflection Biosciences Limited. J. Seoane: Advisory/Consultancy, Research grant/Funding (self): Mosaic Biomedicals; Leadership role: Northern Biologicals; Research grant/Funding (self): Roche Glycart AG; Research grant/Funding (self): Ridgeline; Research grant/Funding (self): Isarna Therapeutics; Research grant/Funding (self): Hoffmann-La Roche LTD. E. Elez: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman La - Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Servier, Amgen; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Array Biopharma; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck Sharp & Dohme Corp.; Honoraria (institution): Array Biopharma; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): Hoffman La-Roche; Honoraria (institution): Merck Sharp & Dohme Corp.; Honoraria (institution): Bristol Myers Squibb; Honoraria (institution): Abbvie, Amgen; Honoraria (institution): Novartis; Honoraria (institution): GlaxoSmithKline; Honoraria (institution): Astrazeneca; Research grant/Funding (institution): Merck Sharp & Dohme Corp.; Research grant/Funding (institution): Sanofi. All other authors have declared no conflicts of interest.