scholarly journals AB054. SOH21AS148. Novel insights into immune-independent functions of immune checkpoint inhibitors in oesophageal adenocarcinoma—potential implications for overcoming chemoresistance to first-line chemotherapy regimens

2021 ◽  
Vol 5 ◽  
pp. AB054-AB054
Author(s):  
Maria Davern ◽  
Croi Ellen Buckley ◽  
Claire Fitzgerald ◽  
Aisling Heeran ◽  
Noel Donlon ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Oesophageal Adenocarcinoma ◽  
First Line ◽  
Independent Functions ◽  
Line Chemotherapy

scholarly journals First-Line Chemotherapy Response Is a Predictive Factor for Immune Checkpoint Inhibitors Treatment in Advanced Urothelial Carcinoma, a Real World Retrospective Study

2021 ◽  
Author(s):  
Jian-Ri Li ◽  
Shian-Shiang Wang ◽  
Kevin Lu ◽  
Chuan-Shu Chen ◽  
Chen-Li Cheng ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
The Other ◽  
Chemotherapy Response ◽  
First Line ◽  
Advanced Urothelial Carcinoma ◽  
Line Chemotherapy

Abstract Background: Immune checkpoint inhibitors (ICIs) have become important tools for the treatment of advanced urothelial carcinoma (aUC). However, the clinical strategy using ICIs and chemotherapy is still controversy. The aim of this study was to evaluate the association of clinical parameters in aUC patients with ICIs treatment.Methods: We retrospectively analyzed aUC patients who received atezolizumab and pembrolizumab between January 2015 and October 2020. The associations between baseline demographics and clinical outcomes were evaluated.Results: Of the 74 included patients, the median age was 67 years. Among them, 53 patients received atezolizumab and the other 21 received pembrolizumab. There were 50 patients receiving first line ICIs therapy and the other 24 received second line monotherapy. Fifty-two (83.87%, 52/62) received cisplatin among all chemotherapy patients. The median progression free survival was 10.94 months and the overall survival was 28.44 months. Poor chemotherapy response or no chemotherapy, liver metastases, Eastern Cooperative Oncology Group (ECOG) status and higher neutrophil/lymphocyte ratio (NLR) were associated with higher risk of diseases progression (HR=5.70, 95% CI 2.04-15.90, p=0.001, HR=6.08, 95% CI 1.79-20.57, p=0.004; HR=5.40, 95% CI 1.76-16.57, p=0.003; HR=6.08, 95% CI 2.56-14.44, p<0.001 and HR= 1.02, 95% CI 1.01-1.03, P=0.002 respectively). Liver metastases and WBC before ICI were associated with increased death risk (HR=11.95, 95%CI 3.22-44.34, p<0.001; HR=1.0001, 95% CI 1.00001-1.00002, p=0.036 respectively) while ICI response was associated with decreased death (HR=0.22, 95%CI 0.08-0.62, p=0.004). Chemotherapy responders were associated with better ICI treatment response (OR=6.52, 95%CI 1.45-29.24, p=0.014) while lymph node metastases and poor ECOG was associated with poor ICI response (OR=0.31, 95%CI 0.10-0.94, p=0.038; OR=0.32, 95%CI 0.11-0.95, p=0.040).Conclusions: Our data showed predictive role of first-line chemotherapy response to ICIs treatment efficacy in aUC patients as well as other prognostic factors, such as ECOG status, serum white blood cell count or NLR and liver metastases.

scholarly journals P09.07 Novel insights into immune-independent functions of immune checkpoint inhibitors in oesophageal adenocarcinoma; potential implications for designing combination immuno-chemotherapy regimens to achieve synergistic responses

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A31-A31
Author(s):  
M Davern ◽  
C Buckley ◽  
C Fitzgerald ◽  
AB Heeran ◽  
NE Donlon ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dna Repair ◽  
Western Blot ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Oesophageal Adenocarcinoma ◽  
Standards Of Care ◽  
Independent Functions

BackgroundImmune checkpoint inhibitors (ICIs) reinvigorate anti-tumour immunity in oesophageal adenocarcinoma (OAC). However, emerging studies have identified novel immune-independent functions for immune checkpoints (ICs) in other solid tumour-types, whereby IC-intrinsic signalling in gastric cancer cells confers chemoresistance. This study explores immune-independent functions of ICs in OAC and if therapeutic blockade may enhance chemotherapy toxicity.Materials and MethodsOAC cells were screened in vitro and in vivo (n=14 OAC human tissue biopsies) for a range of ICs (PD-1,TIGIT,TIM-3,LAG-3,A2aR,PD-L1,PD-L2,CD160) by flow cytometry. The phenotype of OAC cells expressing ICs was also assessed for features of stemness (ALDH, CD54), senescence (β-galactosidase) and invasiveness (vimentin) in the absence and presence of chemotherapy by flow cytometry. OAC cells were also treated with chemotherapy in the absence and presence of a MEK inhibitor to determine if MEK signalling regulated IC expression. Importantly, the effect of ICIs on the hallmarks of cancer in OAC cells was assessed which included: OAC cell viability (CCK-8 assay and western blot to assess Bcl-xL and Bcl-2 levels), proliferation (BrdU assay and ki67 expression by intracellular flow cytometry), chemo-sensitivity (annexin-V propidium iodide assay and cell cycle analysis by flow cytometry and expression of chemotherapy efflux and influx pumps by western blot: ATP7a, ATP7b, CTR1 and ABCB9), metabolism (seahorse), invasiveness and stemness characteristics (vimentin and aldefluor assay, respectively by flow cytometry) and DNA repair (γH2ax by flow cytometry to assess levels of DNA repair and the expression of DNA repair genes were quantified by qPCR: MLH1, SMUG1, PARP1, MMS19) was assessed in OAC cells.ResultsA subpopulation of stem-like, senescent and vimentin+ OAC cells were enriched for ICs, which was enhanced by FLOT and CROSS chemotherapy regimens. IC expression increased on the surface of OAC cells 48h post-chemotherapy treatment and was sustained up to 3 weeks post-treatment in vitro. Inhibition of pro-survivla MEK signalling reduced chemotherapy-induced upregulation of ICs. Blockade of PD-1, TIGIT, A2aR, TIM-3 and PD-L1 decreased proliferation, DNA repair, induced apoptosis and enhanced toxicity of FLOT in OAC cells. Blockade of TIGIT decreased pro-survival Bcl-xL factor, induced cell death and promoted a more glycolytic phenotype in OAC cells.ConclusionsSeveral novel ICs have been identified as potential targets to enhance chemotherpay efficacy in OAC. Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance for stem-like, senescent and vimentin+ aggressive cancer cell clones. Combining ICIs with chemotherapy may synergise with chemotherpay in OAC patients via immune-independent mechansims and boost response rates to current standards of care. Further studies are warranted through clincal trials to further establish synergistic ICI-chemotherapy combinations in OAC.Disclosure InformationM. davern: None. C. Buckley: None. C. Fitzgerald: None. A.B. Heeran: None. N.E. Donlon: None. J. McGrath: None. R. O’ Brien: None. F. O’ Connell: None. B. Murphy: None. N. Lynam-Lennon: None. J.V. Reynolds: None. S.G. Maher: None. A.D. Sheppard: None. A. Bhardwaj: None. A. Bhardwaj: None. C. Butler: None. N. Ravi: None. J. Lysaght: None.

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