Immune escape mechanism behind resistance to anti-PD-1 therapy in gastrointestinal tract metastasis in malignant melanoma patients with multiple metastases

Immunotherapy targeting the PD-1 axis has recently become a standard treatment for patients with malignant melanoma. However, approximately 25% of reported malignant melanoma patients who initially responded to immunotherapy with anti-PD-1 mAb had progressive disease, and the immune escape mechanism behind resistance to anti-PD-1 therapy is not yet fully understood in the clinical setting. In the present study, we included four malignant melanoma patients, in whom multiple metastases other than gastrointestinal tract metastasis had disappeared or were controlled under multidisciplinary treatment that included anti-PD-1 therapy. Using IHC, we evaluated the immune status of surgically resected specimens of gastrointestinal tract metastases as acquired resistant lesion to anti-PD-1 therapy. We herein report that the down-regulated expression of HLA class I and up-regulated expression of inhibitory immune checkpoint ligands, CD155 (ligand for T cell immunoglobulin and ITIM domain, TIGIT) and carcinoembryonic antigen-related adhesion molecule-1 (ligand for TIM-3), were observed on the tumor cells in the metastatic gastrointestinal tract tumors. Moreover, our results also suggest that stromal TGF- β may be related to this down-regulation of HLA class I expression on the tumor cells. In conclusion, it is likely that the down-regulated expression of HLA class I and additional expression of inhibitory immune checkpoint ligands other than PD-L1 on the tumor cells were acquired in the gastrointestinal tract metastasis during anti-PD-1 therapy in the malignant melanoma patients.