(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.