Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer

Abstract

Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma (PDAC) tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFNγ to promote inducible nitric oxide synthase (iNOS) expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII+CD80+CD86+ M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalize its potential use to target immune evasion in pancreatic cancer.

High Capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of Lung Adenocarcinoma

“…The anti-tumor activity of macrophages ensues partly from NOS2 expression. NOS2 encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes the production of tumoricidal reactive oxygen species (8). While the expression level of IL-6, IL-1b, and NOS2 for the Resiquimod and LPS treatment groups were considerably enhanced, TNF-α expression was relatively modest.…”

“…Signaling interactions between cancer cells and neighboring immune cells lead to the protumorigenic evolution of the latter, yielding cells that lack anti-tumor properties (7). For instance, a major proportion of the tumorassociated macrophages (TAMs) display an alternatively activated endotype, causing a shift in the Th1/Th2 cytokine balance towards a more Th2-like (anti-inflammatory) activity, rendering an immunosuppressive niche conducive to tumor growth (8). Additionally, TAMs can dampen the adaptive immune response by impeding the tumor infiltration of CD8+ cytotoxic T cells (9).…”

Nanomedicine applications in the treatment of breast cancer: current state of the art

“…Table 7B lists the nanodelivery systems that may achieve anticancer effects via macrophages. [95][96][97] Interestingly, it was found that a part of Abraxane's activity may be derived from its activity in increasing the CD80 + CD86 + M1 macrophage subpopulation that works in an antagonistic manner to the M2 subpopulation. 95 Regardless, macrophage-based nanotherapy remains in exploratory stage and more studies are needed to substantiate its potential.…”

The pancreatic cancer microenvironment: A true double agent

“…114,115 Additionally, there is work citing that the efficacy of nab-paclitaxel is actually dependent upon drug internalization by TAMs via macropinocytosis. 116 There are currently clinical trials in PDAC forthcoming utilizing vitamin D analogs as a stromal remodeling mechanism (NCT02930902, NCT02030860).…”

“…However, the levels of SPARC expression did not appear to correlate with response to treatment . Additionally, there is work citing that the efficacy of nab ‐paclitaxel is actually dependent upon drug internalization by TAMs via macropinocytosis . Therefore, targeting the optimization of macropinocytosis may be an additional option to improving nab ‐paclitaxel efficacy.…”