Immune microenvironment profiling of gastrointestinal stromal tumors (GIST)

Background: GIST benefit from TK inhibitors but unfortunately can develop resistance or intolerance. Patients prolonged life expectancy associated with the complex biology involved in progressive disease led to a growing urgency and interest in developing new therapeutic strategies. Recently, few preclinical studies were conducted investigating the immunological profile in GIST. In the present study we analyzed GIST by whole transcriptome sequencing to estimate the gene expression signature, the presence of immune-infiltrate through in silico analysis, and to define the immunological profile of GIST as basis for immunotherapy . Methods: 18 fresh frozen GIST tumors (14 primary and 4 metastases) were analyzed. RNA-seq was performed with Illumina technology. Gene expression data was used to estimate the relative and absolute presence of 22 hematopoietic cell types in tumor microenvironment adopting CIBERSORT, an analytical tool suited to perform a deconvolution of neoplastic and tumor-infiltrating cells. The data were further processed to evaluate the enrichment of immune cell types, the correlation between cell subpopulations and to compare GIST microenvironment with other tumors. IHC tests for CD163, CD20, CD8 and TIA1 were performed and scored on FFPE samples. Results: A significant presence of immune-infiltrate in all GIST samples was confirmed, with a dominance of macrophages (M2 and M1), immediately followed by CD3+ T cells, both CD4+ and CD8+. Compared to other solid tumors, the immune profile of GIST appears similar to that of melanoma. The most relevant result is the high amount of CD8+ T-cells, suggesting that the adaptive immune response could be an immunotherapeutic target. The presence of CD8+ was confirmed by IHC that also showed the expression of citolytic markers (TIA1). Moreover the abundance of CD8+ T-cells correlated with the expression of IFN-gamma signature genes. Interestingly, the abundance of macrophages negatively correlates with T-cells presence (CD4+ and CD8+) supporting the dynamic balance between the immunosuppressive and active components of the immune-infiltrate. Conclusions: These findings represent a potential rationale to plan an immunotherapy approach along with TK inhibitors in GIST