Checkpoint inhibitors in pancreatic cancer

Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer

“…30 31 Although PD1 immune checkpoint blockade has shown promise in cancer therapy and induced durable responses in several tumor types, its efficacy is limited for patients with PC. 11 In the present study, the murine model of PC presented here also illustrates the limitations of PD1 checkpoint blockade as a singleagent treatment. Tumor development was completely inhibited when anti-PD1 treatment began at the time of tumor inoculation but had only minor effects on established tumors.…”

“…[35][36][37] Despite the progress of combinatorial treatment with PD1 blockade in melanoma or non-melanoma solid cancers, PC has proven refractory to PD1 checkpoint-based immunotherapy even when combined with chemotherapy (capecitabine, gemcitabine or nab-paclitaxel) or combined with other immunotherapy (tremelimumab: antibody targeting CTLA-4; acalabrutinib: bruton tyrosine kinase inhibitor; mogamulizumab: antibody targeting CC chemokine receptor 4; cabiralizumab: antibody targeting CSF-1 receptor). 11 These pieces of clinical evidence encourage us to pay more attention to combinations of checkpoint inhibitors with other modalities that could potentially change the tumor-generated TME or target other mechanisms of immune escape.…”

“…The potential for clinical application of these findings is notable because there are currently no clinically relevant evidence to show that anti-PD1 immunotherapy is effective in treating PC. 11 Conversely, IFN-γ is also not approved for the treatment of any cancer, although studies showed improved survival when IFN-γ was administered to patients with bladder carcinoma, malignant melanoma and advanced ovarian carcinoma. 43 In the present study, we reported that IFN-γ suppresses the expression and secretion of tumor-derived CXCL8, which inhibits tumor-infiltrating of CXCR2 + CD68 + macrophages by blocking the CXCL8-CXCR2 axis.…”

“…[4][5][6][7] Tumor expression of programmed death-ligand 1 (PD-L1) inhibits tumor-reactive T cells in PC animal models, and several clinical studies show a close relationship between tumor expression of PD-L1 and adverse outcomes in patients with PC. [8][9][10] Although accumulating evidence suggests that the PD1/PD-L1 axis plays an important role in PC immune escape, clinical application of anti-PD1 therapy alone shows optimistic antitumor effects in a minority of cases, 11 suggesting that other mechanisms also contribute to immune evasion in patients with PC.…”

Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers

“…Commercially available tests also include a panel of genes known to be causative for FPCs. Above all, variants of HR-associated genes [42][43][44][45][46][47][48]55] and mismatch repair genes [56] are often recognized and related to the drug choice (poly ADP-ribose polymerase (PARP) inhibitor [41] and immune checkpoint inhibitor [57], respectively).…”