Abstract
Simple SummaryHER2 may contribute to immune evasion in gastric cancer that is associated with PD-L1 expression. Autologous organoid/immune cell co-cultures serve as an appropriate in vitro model to study the effects of anti-HER2 targeted therapy in combination with anti-PD1 immune checkpoint inhibition and may be used as an ex vivo tool for precision medicine.(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived suppressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.
Highlights
Gastric cancer is the third most prevalent for cancer-related mortality [1,2]
Human epidermal growth factor receptor2 (HER2) Was Significantly Expressed in the Intestinal Subtype of Gastric Cancer and Correlated with a Higher Expression of programmed death-ligand 1 (PD-L1) in the Commercial Gastric Cancer Tissue Microarrays (TMAs)
The immunohistochemistry of a gastric cancer tissue array established a direct correlation between HER2 expression and the expression of PD-L1 in the intestinal-type gastric cancer (Figure 1a,b)
Summary
Gastric cancer is the third most prevalent for cancer-related mortality [1,2]. While there is a relatively low incidence of gastric cancer in the United States due to early diagnosis and treatment of Helicobacter pylori (H. pylori) [3], the 5-year survival rate remains at a dismal 10–30% [4]. Inhibition of the PD-1/PD-L1 axis has led to effective therapeutic responses in different solid cancers, such as melanoma, renal and non-small cell lung cancer [8,9,10,11]. Despite the fact that 35–40% of gastric tumors express PD-L1, immunotherapy responses are relatively low [12,13,14,15,16]. PD-L1 expression does not consistently predict the survival benefit of anti-PD-1 therapy [17]. This evidence drives the need to develop a preclinical in vitro model system to characterize the tumor-immune microenvironment and test for immunotherapy responses of individual patients
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