Targeting Hsp70 Immunosuppressive Signaling Axis with Lipid Nanovesicles: A Novel Approach to Treat Pancreatic Cancer

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F25%3A00080241" target="_blank" >RIV/00209805:_____/25:00080241 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/2072-6694/17/7/1224" target="_blank" >https://www.mdpi.com/2072-6694/17/7/1224</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers17071224" target="_blank" >10.3390/cancers17071224</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Targeting Hsp70 Immunosuppressive Signaling Axis with Lipid Nanovesicles: A Novel Approach to Treat Pancreatic Cancer

Popis výsledku v původním jazyce

BACKGROUND: Despite many efforts to effectively treat PDAC, PDAC carries one of the highest mortality rates of all major cancers. Thus, there is a critical unmet need to develop novel approaches to improve the clinical outcome of PDAC. It is well known that many cancers, including PDAC, generate a local TME that allows cancer to escape normal immune surveillance. Phosphatidylserine (PS), a negatively charged phospholipid that is abundant on the cancer cell membrane and with known actions to promote the secretion of immunomodulatory proteins, may provide a mechanism to regulate the TME. This study explored that possibility. METHODS: MΦ differentiation and polarization were assessed by Western blotting and flow cytometric approaches. PS exposure and surface markers were analyzed by flow cytometry. Protein-protein and protein-lipid interactions were analyzed by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Phospholipid and SapC-DOPG treatment were employed to assess target protein functions in MΦ polarization, tumor growth, and survival in subcutaneous and orthotopic tumor models. The PK-PD and safety of SapC-DOPG were tested on orthotopic mouse models. RESULTS: Our studies show that PDAC secretes Hsp70 that stimulates the MΦ polarization to the immunosuppressive M2 phenotype. We found that high surface PS on cancer cells correlates with increased secretion of Hsp70 and is associated with higher MΦ differentiation activity in vitro and in vivo. Furthermore, blocking cancer cell-secreted Hsp70 with SapC-DOPG reverses the immune suppression and reduces tumor growth. CONCLUSIONS: These preclinical results reveal a novel immunotherapeutic approach to potentially improve the outcome of PDAC treatment in humans.

Název v anglickém jazyce

Targeting Hsp70 Immunosuppressive Signaling Axis with Lipid Nanovesicles: A Novel Approach to Treat Pancreatic Cancer

Popis výsledku anglicky

BACKGROUND: Despite many efforts to effectively treat PDAC, PDAC carries one of the highest mortality rates of all major cancers. Thus, there is a critical unmet need to develop novel approaches to improve the clinical outcome of PDAC. It is well known that many cancers, including PDAC, generate a local TME that allows cancer to escape normal immune surveillance. Phosphatidylserine (PS), a negatively charged phospholipid that is abundant on the cancer cell membrane and with known actions to promote the secretion of immunomodulatory proteins, may provide a mechanism to regulate the TME. This study explored that possibility. METHODS: MΦ differentiation and polarization were assessed by Western blotting and flow cytometric approaches. PS exposure and surface markers were analyzed by flow cytometry. Protein-protein and protein-lipid interactions were analyzed by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Phospholipid and SapC-DOPG treatment were employed to assess target protein functions in MΦ polarization, tumor growth, and survival in subcutaneous and orthotopic tumor models. The PK-PD and safety of SapC-DOPG were tested on orthotopic mouse models. RESULTS: Our studies show that PDAC secretes Hsp70 that stimulates the MΦ polarization to the immunosuppressive M2 phenotype. We found that high surface PS on cancer cells correlates with increased secretion of Hsp70 and is associated with higher MΦ differentiation activity in vitro and in vivo. Furthermore, blocking cancer cell-secreted Hsp70 with SapC-DOPG reverses the immune suppression and reduces tumor growth. CONCLUSIONS: These preclinical results reveal a novel immunotherapeutic approach to potentially improve the outcome of PDAC treatment in humans.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

<a href="/cs/project/GA22-17102S" target="_blank" >GA22-17102S: Mechanismy udržování proteinové homeostázy v nádorech.</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cancers

ISSN

—

e-ISSN

2072-6694

Svazek periodika

17

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

22

Strana od-do

1224

Kód UT WoS článku

001464680600001

EID výsledku v databázi Scopus

2-s2.0-105002616479