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

Abstract

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting.

Harnessing cytokine-induced killer cells to accelerate diabetic wound healing: an approach to regulating post-traumatic inflammation

“…CIK cells were successfully generated and proliferated in vitro to achieve a CIK cell [ 27 ] percentage that yielded a CD3 + CD56 + value of 46% ( Figure 6A ). To assess the effect of CIK cells in the AGE microenvironment, we used a CCK-8 assay to analyze the performance of HUVECs and fibroblasts indirectly co-cultured with CIK cells.…”

Combination Therapy of Irreversible Electroporation and Cytokine-Induced Killer Cells for Treating Mice Bearing Panc02 Pancreatic-Cancer Xenografts

“…The killing effect of CIK cells on tumors is characterized by high efficiency and lack of major histocompatibility complex (MHC) restriction [17]. CIK cells have good synergistic effects with other adjuvant therapies and the advantages of strong antitumor activity, wide antitumor spectrum, and no obvious adverse reactions [18][19][20]. Studies have shown that adaptive therapy with CIK cells is currently the best cellular-immunotherapy regimen for solid tumors and has a good therapeutic effect on a variety of tumors, especially liver cancer and leukemia [21,22].…”

Clinical Applications of Combined İmmunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review

“…Several stromal or intracellular mechanisms implicated in the synergistic activity have been identified. As mentioned above cytokines and cytotoxic agents improve immunemediated cell killing through TME modulation not only by decreasing the ratio of Tregs, but also by induction of a memory effector cell response (102,104) or direct anti-tumor effect by blockade of cytokine-receptors (105). Co-incubation with dendritic cells has yielded a higher percentage of CD3, CD4 (+) helper T and CD8 (+) T cell accumulation in cell cultures, resulting in improved antiproliferative and cytotoxic effects not only through induction of immune-mediated cell killing, but also direct activation of CIK cells through CCR5 signaling (115,116).…”

“…Favorable outcomes achieved with CIK cell therapy led to increased efforts to improve efficacy with combined approaches. There exists strong preclinical evidence on the synergistic efficacy of proinflammatory cytokines such as interleukins (101)(102)(103)(104) and interferon (105) as well as cytotoxic agents (106), novel small molecule inhibitors (107)(108)(109), immune checkpoint inhibitors (110)(111)(112), monoclonal antibodies (113,114) and dendritic cell (115)(116)(117) or viral-based vaccines (118-120) combined with adoptive cell therapy. Several stromal or intracellular mechanisms implicated in the synergistic activity have been identified.…”