Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8 ⁺ T cell number and tumour growth in pancreatic cancer

CAF-Derived IL6 and GM-CSF Cooperate to Induce M2-like TAMs–Letter

“…In several mice models, BAG3, released by PDAC cells, binds to TAMs, stimulating their protumor activity; a BAG3-blocking antibody impairs tumor growth and the metastatic spread (4,5). We have now verified whether CAFs are also involved in the anti-BAG3 effect, in two of the previously studied models (4,5): two experiments in allografts of a murine pancreatic cancer cell line in syngeneic mice; and an experiment in patient-derived PDAC xenografts in immunodeficient mice. In both models, we have detected a high downmodulation in the expression of the CAF activation marker a-SMA in anti-BAG3treated mice compared with controls ( Fig.…”

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

“…Preclinical work has demonstrated that tumor-associated macrophages (TAMs) and monocytic and granulocytic myeloid-derived suppressor cells (MDSCs) contribute to the immunosuppressive tumor microenvironment (TME) of pancreatic cancer [17]. In PDAC mouse models, inhibition of colony-stimulating factor 1 (CSF1) or Anti-PD-1 mAb IP 10 mg/kg 2× per week on D10 after inoculation Anti-BAG3 antibody IP 20 mg/kg 3× per week on D10 after inoculation Mice mt4-2D [20] ICI immune checkpoint inhibitor, PD-L1 programmed death ligand 1, mAB monoclonal antibody, IP intraperitoneal, D day, CXCL12 chemokine (C-X-C motif ) ligand 12, CTLA-4, cytotoxic T-lymphocyte associated protein 4, PD-1 programmed cell death protein 1 receptor, CSF1/CSF1R colony-stimulating factor 1/colony-stimulating factor 1 receptor, OT-1 ovalbumine, GVAX allogeneic pancreatic tumor cells transfected with granulocytemacrophage colony-stimulating factor (GM-CSF) gene, SC subcutaneous, FAK focal adhesion kinase, IV intravenous, CXCR2 C-X-C chemokine receptor type 2, RT radiation therapy, Gy gray, MLL1 mixed-lineage leukemia 1,…”

“…Targeting of either the H3K4 methylation-specific histone methyltransferase, mixed-lineage leukemia 1 (MLL1), with the epigenetic agent verticillin A, JAK/ STAT pathway with ruxolitinib, mitogen-activated protein kinase (MAPK) pathway with a MAPK kinase (MEK inhibitor, cholecystokinin (CCK) receptor, DNA methyltransferase with decitabine, or Bcl-2 in combination with checkpoint blockade significantly enhanced tumor growth suppression, when compared to controls, in pancreatic cancer-carrying mouse models [19][20][21][22][23][24]. MLL1 normally catalyzes the trimethylation of H3K4 to activate immune inhibitory PD-L1 transcription in tumor cells [19].…”

“…This prompted the addition of PD-1 antibody following decitabine treatment that showed greater suppression of tumor growth compared to either agent alone in PDAC mice [24]. Lastly, blocking of Bcl-2-Associated athano-Gene 3 (BAG3) has been shown to decrease the number of immunosuppressive TAMs in PDAC [20].…”

CAF-Derived IL6 and GM-CSF Cooperate to Induce M2-like TAMs–Response

“…We read with great interest the letter by Iorio and colleagues entitled "Cancer-stimulated CAFs enhance monocyte differentiation and pro-tumoral TAM activation" in this issue of Clinical Cancer Research, which provides valuable context and additional discussion of our recent article in this journal. In their letter, the authors reevaluated their recent work on the role of BAG3, a regulator of chaperone-assisted selective autophagy, which inhibits tumorigenesis and metastasis in pancreatic ductal adenocarcinoma (1,2). They report reductions in cancer-associated fibroblast (CAF) activation and lowered collagen deposition in both syngeneic and patient-derived xenograft models of pancreatic cancer treated with BAG3 antibodies.…”