Oncogenic KIT Modulates Type I IFN–Mediated Antitumor Immunity in GIST

Abstract

Type I interferons (IFN) are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8 + T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to HLA class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling while KIT inhibition attenuates tumor immunogenicity and is party rescued by innate immune stimulation.

Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

“…reported that KIT signalling contributes to the type I interferon pathway, whereas KIT inhibition attenuates tumour immunogenicity. In their mouse model, inhibition of oncogenic KIT in GIST reduced type I interferon production [63] . Interestingly, although a recent study excluded imatinib use as an anti SARS-Cov-2 drug [64] , this compound has been shown to reduce the expression of genes with “proviral” functions, including Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 gene ( CEAMCAM1 ) [65] .…”

Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers

“…On the other hand, imatinib also induces immunosuppressive microenvironment. For instance, imatinib drives intratumoral macrophage M2 polarization [ 116 ], induces M1 macrophages to secrete anti-inflammatory cytokine IL-10 [ 97 ] and lowers MHC-I expression [ 99 , 195 ]. Moreover, chronic imatinib therapy decreases the number of intratumoral CD8 + T cells and DC cells [ 191 ], and thus weakens the antitumor immune responses.…”

“…The expression of MHC-I molecules in GIST is highly heterogeneous, which was further decreased by the weakened type I interferons (IFNs) signaling mediated by imatinib treatment [ 99 , 195 ]. In patients receiving imatinib treatment, up to 30% of GISTs completely lose and about 40% of GISTs displayed localized loss of MHC-I expression [ 99 ].…”

“…In patients receiving imatinib treatment, up to 30% of GISTs completely lose and about 40% of GISTs displayed localized loss of MHC-I expression [ 99 ]. Moreover, in Kit V558Δ/ + GIST mice, Liu et al reported that imatinib reduced the expression of MHC-I molecules by inhibiting type I IFNs production and signaling, attenuated tumor immunogenicity, decreased the infiltration of CD8 + T cells, and thus weakening the antitumor immune responses [ 195 ], which may partially explain the limited efficacy of immunotherapy for GIST patients having received prior imatinib therapy. Considering the role of type I IFNs played in affecting MHC-I expression and thus the antitumor immune responses, type I IFNs signaling has been widely exploited to improve the antitumor effect of imatinib [ 195 ].…”

Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST

“…Clinical studies have been developed to investigate immune checkpoint inhibitors (ICI) activity in GISTs combined with TKI, but none of them managed to show evidence of synergism [ 17 , 18 ]. This is possibly due to the fact that imatinib hampers type I IFN production and can decrease HLA-I expression on tumor cells [ 19 ], with a potentially detrimental role on the efficiency of ICI due to HLA-I expression reduction [ 20 ]; what is more, imatinib can alter intratumoral CD8 + T-cell subtype composition and activity [ 21 ]. Recently, the results of ICI monotherapy with nivolumab vs. nivolumab + ipilimumab in advanced GISTs patients, at least resistant/refractory to imatinib, have been published [ 22 ]: the primary endpoint (response rate > 15%) was not met, neither for nivolumab nor for nivolumab + ipilimumab.…”