Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers

Abstract

Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.

Keywords: Gastrointestinal cancers; Gastrointestinal stromal tumor; Imatinib; Immune checkpoint inhibitors; Immunology; Immunotherapy; Model; Resistance.

Fig. 1

The anatomic and genomic distribution of GIST. A The anatomic locations of primary and metastatic GISTs. Primary GISTs usually originate from stomach and small intestine, and metastasize to liver or peritoneum. B The genomic profiles of GISTs. KIT and PDGFRA signaling are activated by their natural ligands SCF and PDGF respectively in physiological conditions, but are constitutively activated by oncogenic mutations and in a ligand independent manner in GISTs. According to the driver mutations, GISTs can be broadly classified as KIT-mutant GISTs, PDGFRA-mutant GISTs and KIT/PDGFRA-WT GISTs, and the last one could be further divided into SDH-deficient and SDH-competent GISTs based on the expression of succinate dehydrogenase. GIST: gastrointestinal stromal tumor; PDGFRA: platelet-derived growth factor receptor alpha; WT: wild type; EC: ligand-binding extracellular domain; TM: transmembrane domain; JM: intracellular juxtamembrane domain; TK: tyrosine kinase domain; SDH: succinate dehydrogenase; SCF: stem cell factor; PDGF: platelet-derived growth factor

Fig. 2

The immune microenvironment of GIST. A GIST is mainly infiltrated with T cells and M2 macrophages, and less frequently by NK, B and DC cells. Approximately half of the GISTs harbor intratumoral tertiary lymphoid structures which were enriched with T cells and B cells. B Gross comparisons of the immune cell infiltration between different groups. Immune cells seem to be enriched in metastatic GIST (especially liver metastasis), non-gastric GIST and PDGFRA-mutant GIST and the margin area of the GIST. GIST: Gastrointestinal stromal tumor; NK: natural killer cell; MΦ: macrophages; M1: M1 that macrophages are classically activated; M2: M2 macrophages that are alternatively activated; DC: dendritic cell; Th1: T helper type 1 cell; Th2: T helper type 2 cell; γδ T cell: gamma delta T cell with T cell receptors (TCRs) composed of γ- and δ-chains

Fig. 3

The immunomodulatory effects of imatinib in GIST. A The general immunological effects of imatinib in GIST. Short-term administration of imatinib enhanced the antitumor immune response via increasing the infiltration and activity of immune cells and the secretion of IFNγ. While, long-term usage of imatinib may weaken the antitumor immune response by enriching the M2 macrophages and decreasing the amounts of CD8⁺ T and DC cells, as well as the expression of MHC-I molecules. B Dissected immunological effects of imatinib on various types of cells within the GIST, including GIST cells, CD8⁺ T cells, γδ T cells, Treg cells, NK cells, Macrophages and DC cells. GIST: gastrointestinal stromal tumor; DC: dendritic cell; NK: natural killer cell; IFNγ: interferon gamma; PD-L1: programmed death-ligand 1; MHC-I: major histocompatibility complex class I; IDO: indoleamine 2,3-dioxygenase; Treg: regulatory T cells; MΦ: macrophages; γδ T cell: gamma delta T cell with T cell receptors (TCRs) composed of γ- and δ-chains

Fig. 4

Immunotherapy strategies reported for GIST in literatures. The mostly studied immunotherapies for GIST are immune checkpoint inhibitors and cytokine therapies. Antibodies, antibody–drug conjugates, vaccines and adoptive cell therapies have also been widely evaluated in clinical or preclinical experiments in GIST. New emerging immunotherapy targets, such as WT1, CTA, CSPG4, LAG3, VISTA, Gal-9 and Tim-3, may also be exploited to develop antibody drugs or cell products to treat GIST in future. GIST: gastrointestinal stromal tumor; DC: dendritic cell; MHC-I: major histocompatibility complex class I; TCR: T cell receptors; CTLA-4: cytotoxic T-lymphocyte antigen 4; PD1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; CIK: cytokine-induced killer cell; NKG2D: natural killer group 2 member D; MICA/B: MHC class I chain-related protein A and B; CAR-T: chimeric antigen receptor T; PHA: phytohemagglutinin; GPR20: G protein-coupled receptor 20; SSTR2: somatostatin receptor 2; VEGF: vascular endothelial growth factor; MΦ: macrophages; VISTA: V-type immunoglobulin (Ig) domain-containing suppressor of T-cell activation; Tim-3: T cell immunoglobulin and mucin-domain containing-3; LAG3: lymphocyte activation gene-3; CSPG4: chondroitin sulfate proteoglycan 4; Gal-9: Galectin-9; WT1: Wilms tumor protein 1; CTA: cancer testis antigen

Fig. 5

Models for GIST research in literatures. Cell lines, CDX, PDX and genetically engineered mouse models are the most frequently used models. chicken embryo model and the duodenal reflux induced rat model have been reported for GIST but haven't been widely applied. Organoid models are emerging and hold brilliant future. CDX: cell line-derived xenograft; PDX: patient-derived xenograft