dc.contributor.author |
Győri, Dávid Sándor |
|
dc.contributor.author |
Lim, EL |
|
dc.contributor.author |
Grant, FM |
|
dc.contributor.author |
Spensberger, D |
|
dc.contributor.author |
Roychoudhuri, R |
|
dc.contributor.author |
Shuttleworth, SJ |
|
dc.contributor.author |
Okkenhaug, K |
|
dc.contributor.author |
Stephens, LR |
|
dc.contributor.author |
Hawkins, PT |
|
dc.date.accessioned |
2021-04-06T11:21:02Z |
|
dc.date.available |
2021-04-06T11:21:02Z |
|
dc.date.issued |
2018 |
|
dc.identifier.citation |
journalVolume=3;journalIssueNumber=11;pagination=e120631, pages: 12;journalTitle=JCI INSIGHT;journalAbbreviatedTitle=JCI INSIGHT; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/7331 |
|
dc.identifier.uri |
doi:10.1172/jci.insight.120631 |
|
dc.description.abstract |
Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kdelta, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kdelta-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies. |
|
dc.relation.ispartof |
urn:issn:2379-3708 |
|
dc.title |
Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy |
|
dc.type |
Journal Article |
|
dc.date.updated |
2019-07-30T09:34:35Z |
|
dc.language.rfc3066 |
en |
|
dc.rights.holder |
NULL |
|
dc.identifier.mtmt |
3385661 |
|
dc.identifier.wos |
000434866600017 |
|
dc.identifier.pubmed |
29875321 |
|
dc.contributor.department |
SE/AOK/I/Élettani Intézet |
|
dc.contributor.institution |
Semmelweis Egyetem |
|