Normalizing tumor blood vessels may paradoxically suppress immune attacks on cancer
Researchers found that stabilizing leaky tumor blood vessels—a common strategy to improve drug delivery—triggers immune-suppressive signals in endothelial cells. The discovery suggests doctors may need to combine vascular normalization with immunotherapy to avoid inadvertently protecting tumors from immune attack, reshaping oncology treatment protocols.
Originaltitel: Vascular normalization in breast cancer confers an endothelial immune suppressive gene expression profile
Normalisering av tumörblomdkärl kan blocka immunresponsen — en upptäckt från Uppsala universitet som utmanar strategier för immunterapeutisk behandling av bröstcancer. Forskare vid Uppsala universitet identifierade att när endotelceller i bröstcancersvulster saknar proteinet Shb uppstår täta blodkärl med ett immunsuppressivt genuttrycksmönster. Det normaliserade endotelet liknade friskt bröstvävnads kärlväggar snarare än tumörvävnadens läckande kärl — men försvagade ändå immunförsvaret. Studien jämförde genexpression i normaliserade musmusstrukturer med frisk human bröstvävnad och cancervävnad. Samma immunsuppressiva profil återfanns i friska lung- och tjocktarmsöd, medan motsvarande cancerväv visade starkare immunresponser. Resultatet föreslår ett motsäkulturproblem: normaliserade kärl kan bli barriärer mot immunterapi. För utvecklare av cancerbehandlingar innebär det att ren kärlnormalisering utan immunaktivering kan motverka effekten.
Tumors commonly exhibit a leaky vasculature and innate and/or adaptive immune cell infiltration. A recent study showed that a non-leaky and normalized mouse breast cancer vasculature after conditional deletion of the Shb gene in endothelial cells (EC) displayed a suppressive immune cell profile. To extend those findings further, regulation of immunomodulatory gene expression of normalized breast cancer EC was related to healthy human breast and human breast cancer EC gene expression. A considerable correlation was observed in the gene expression profiles of immunoregulatory genes between normal breast arterial EC and normalized (Shb-deficient) EC, and these changes did not primarily seem to involve gene products forming conduits for tumor leukocyte transendothelial migration but other aspects of immune suppression as for example cytokine expression. In addition to breast cancer, healthy lung and colonic EC exhibited an immune suppressive phenotype compared to their lung cancer and colorectal cancer counterparts. It is concluded that normalized EC may confer a non-leaky and immune suppressed phenotype, an insight that may be exploited to enhance the efficacy of immunotherapy.