Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

Abstract

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Patterns of Response and Survival According to the Presence of Hepatic and Extrahepatic Metastasis

“…Mechanistically, macrophages induce apoptosis of CD8+ T cells in the immunosuppressive microenvironment of the liver through fas-ligand binding. This results in an elimination of CD8+ T cells possibly explaining ineffective tumor control and poor response to immunotherapy [13][14][15]. The comparison of CM to UM liver metastases has demonstrated that there is no difference in the extent of immune infiltration, but UM showed a higher ratio of exhausted CD8+ T cells to cytotoxic T cells, total CD8+ T cells, and Th1 cells.…”

DNA Damage Repair Profiles Alteration Characterize a Hepatocellular Carcinoma Subtype With Unique Molecular and Clinicopathologic Features

“…Mast cell and neutrophil cell were specifically enriched in the DDR-suppressed subgroup. Tumor-infiltrating mast cells have been identified as being associated with resistance to anti-PD-1 therapy ( 31 ). These findings have shown that DDR subtypes have distinct immune cell infiltration differences, which hints at different immunotherapy responses between subtypes.…”

Mast Cells: A New Frontier for Cancer Immunotherapy

“…There is also growing awareness that mast cells are a biomarker and important determinant of cancer treatment responses. We recently demonstrated that higher pre-treatment mast cell infiltration is significantly associated with poor responses to pre-surgical chemotherapy in an aggressive form of localized breast cancer [ 7 ], and recent data show that higher mast cell tumor infiltration predicts poor responses to anti-PD-1 ICB in melanoma [ 30 ]. Mast cells can accumulate in cancers due to various growth factors and chemokines, including stem cell factor (SCF), vascular endothelial growth factor (VEGF), CCL2, IL-8, complements, and PGE2 [ 21 , 31 ].…”

“…In contrast to the limited success with monotherapy studies, recent studies focusing on the immunomodulatory impact of mast cells suggest that depleting mast cells may synergize with other immunotherapeutics to most effectively control tumor growth. Using a humanized mouse model of melanoma, Somasundaram et al identified that after PD-1 blockade, mast cells co-localize with T regulatory cells in regions of the tumor with reduced Granzyme B+ CD8+ immune cells and decreased HLA-class I expression, indicating a potential mechanism of resistance to PD-1 blockade [ 30 ]. While PD-1 blockade alone led to partial tumor control, complete regression of melanoma tumors was seen after depleting mast cells with sunitinib or imatinib.…”