Glioblastoma multiforme (GBM) is the most common adult primary brain malignancy, with dismal survival rates of ~14.6 months. The current standard-of-care consists of surgical resection and chemoradiotherapy, however the treatment response is limited by factors such as tumour heterogeneity, treatment resistance, the blood–brain barrier, and immunosuppression. Several immunotherapies have undergone clinical development for GBM but demonstrated inadequate efficacy, yet future combinatorial approaches are likely to hold more promise. Olaparib is FDA-approved for BRCA-mutated advanced ovarian and breast cancer, and clinical studies have revealed its utility as a safe and efficacious radio- and chemo-sensitiser in GBM. The ability of Olaparib to enhance natural killer (NK) cell-mediated responses has been reported in prostate, breast, and lung cancer. This study examined its potential combination with NK cell therapies in GBM by firstly investigating the susceptibility of the GBM cell line T98G to NK cells and, secondly, examining whether Olaparib can sensitise T98G cells to NK cell-mediated responses. Here, we characterise the NK receptor ligand profile of T98G cells and demonstrate that Olaparib does not dampen T98G susceptibility to NK cells or elicit immunomodulatory effects on the function of NK cells. This study provides novel insights into the potential combination of Olaparib with NK cell therapies for GBM.

Purpose Natural killer (NK) cell dysfunction has been extensively reported in obesity and cancer. In the setting of obesity-associated cancers such as oesophagogastric adenocarcinomas (OAC), NK cell therapies offer an opportunity to augment anti-tumour immunity and improve outcomes. Herein, this ex vivo study investigated the potential therapeutic utility of KHYG-1 NK cells for OAC and examined how migration towards and exposure to the omental and tumour microenvironments might hinder their future efficacy. Methods OAC patient-derived tissue conditioned media was used to recapitulate the soluble microenvironments of omentum and tumour. Flow cytometric analysis was performed to compare the function and phenotype of KHYG-1 cells to healthy donor blood-derived NK cells and to assess the effects of the omentum and tumour on KHYG-1 function. KHYG-1 cell chemotaxis towards OAC patient-derived adipose-conditioned media (ACM) or tumour-conditioned media (TCM) was assessed by Boyden Chamber assay. KHYG-1 cell cytotoxicity against target cell line K562 was assessed by NK cell cytotoxicity assay. Results Our functional data reveal that ACM and TCM derived from OAC patients with obesity do not significantly suppress KHYG-1 cell effector function. Furthermore, KHYG-1 cells migrate in significantly higher numbers towards the chemotactic signals of OAC patient-derived omentum, compared to tumour. Interestingly, supplementing the OAC tumour microenvironment (TME) with the chemokine IP-10 enhances KHYG-1 cell chemoattraction. Conclusion Together, our ex vivo data support the therapeutic potential of KHYG-1 cells in OAC. However, our findings suggest that erroneous KHYG-1 cell migration towards omentum will present a future challenge for their effective migration towards OAC tumour in vivo. To overcome this challenge, this study supports the concept of chemokine profile remodelling as an approach to skew KHYG-1 cell migration towards tumour in OAC. Graphical abstract Culture of KHYG-1 with Adipose Conditioned Media (ACM) and Tumour Conditioned Media (TCM) alters the expression of NK cell phenotypic and functional markers while ACM increases their killing capacity. KHYG-1 cell migration towards ACM is significantly higher than their migration towards TCM, however supplementing the TCM with IP-10 increases KHYG-1 cell chemoattraction.