Extracellular HSP110 skews macrophage polarization in colorectal cancer

Abstract

HSP110 is induced by different stresses and, through its anti-apoptotic and chaperoning properties, helps the cells to survive these adverse situations. In colon cancers, HSP110 is abnormally abundant. We have recently showed that colorectal cancer (CRC) patients with microsatellite instability (MSI) had an improved response to chemotherapy because they harbor an HSP110 inactivating mutation (HSP110DE9). In this work, we have used patients' biopsies and human CRC cells grown in vitro and in vivo (xenografts) to demonstrate that (1) HSP110 is secreted by CRC cells and that the amount of this extracellular HSP110 is strongly decreased by the expression of the mutant HSP110DE9, (2) Supernatants from CRC cells overexpressing HSP110 or purified recombinant human HSP110 (LPS-free) affect macrophage differentiation/polarization by favoring a pro-tumor, anti-inflammatory profile, (3) Conversely, inhibition of HSP110 (expression of siRNA, HSP110DE9 or immunodepletion) induced the formation of macrophages with a cytotoxic, pro-inflammatory profile. (4) Finally, this effect of extracellular HSP110 on macrophages seems to implicate TLR4. These results together with the fact that colorectal tumor biopsies with HSP110 high were infiltrated with macrophages with a pro-tumoral profile while those with HSP110 low were infiltrated with macrophages with a cytotoxic profile, suggest that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes associated with HSP110 expression.

Dominant high expression of wild‐type HSP110 defines a poor prognostic subgroup of colorectal carcinomas with microsatellite instability: a whole‐section immunohistochemical analysis

“…Another recent study revealed that the HSP110 expression status is associated with differential polarization of tumor‐associated macrophages in colon cancer. In detail, colon cancer with high expression of HSP110 was associated with infiltration of pro‐tumoral macrophages, whereas colon cancer with low expression of HSP110 was associated with infiltration of anti‐tumoral macrophages . This evidence indicates that HSP110 biologically facilitates the progression of CRCs and supports recent observations that decreased expression of HSP110wt with HSP110 T 17 deletions is associated with an improved prognosis of MSI‐H CRCs.…”

Unconventional Secretion of Heat Shock Proteins in Cancer

“…On the contrary, further work demonstrated inhibittory effects of extracellular HSPH1 and HYOU1 upon macrophage differentiation, favoring a pro-tumor phenotype [10]. …”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…The release of HSP110 from human intestinal epithelial cells has also been described, suggesting a role in the physiological process of epithelial renewal [160]. More recently, we have demonstrated that HSP110, like other HSPs, can be secreted by cancer cells and is abundantly observed in the cancer microenvironment [161]. Interestingly, extracellular HSP110 affects macrophage differentiation/polarization by favoring a protumor, anti-inflammatory profile and the formation of tumor-associated macrophages (TAMs), which are associated with immune suppression.…”

“…Interestingly, extracellular HSP110 affects macrophage differentiation/polarization by favoring a protumor, anti-inflammatory profile and the formation of tumor-associated macrophages (TAMs), which are associated with immune suppression. Furthermore, we found a correlation between the level of extracellular HSP110 and the number of TAMs in patient biopsies [161], suggesting that the effect of extracellular HSP110 function on macrophages may also contribute to the poor outcomes that are associated with HSP110 expression. two forms of HSP110, their differential roles remain unclear.…”