Tumour angiogenesis normalized by myo‐inositol trispyrophosphate alleviates hypoxia in the microenvironment and promotes antitumor immune response

Abstract

Pathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo‐inositol‐trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO2) and stabilizes vessel normalization through activation of endothelial Phosphatase‐and‐Tensin‐homologue (PTEN). Here, we show that the tumour reduction due to the ITPP‐induced modification of the tumour microenvironment by elevating pO2 affects the phenotype and properties of the immune infiltrate. Our main observations are as follows: a relative change in the M1 and M2 macrophage‐type proportions, increased proportions of NK and CD8+T cells, and a reduction in Tregs and Th2 cells. We also found, in vivo and in vitro, that the impaired access of PD1+NK cells to tumour cells is due to their adhesion to PD‐L1+/PD‐L2+ endothelial cells in hypoxia. ITPP treatment strongly reduced PD‐L1/PD‐L2 expression on CD45+/CD31+ cells, and PD1+ cells were more numerous in the tumour mass. CTLA‐4+ cell numbers were stable, but level of expression decreased. Similarly, CD47+ cells and expression were reduced. Consequently, angiogenesis normalization induced by ITPP is the mean to revert immunosuppression into an antitumor immune response. This brings a key adjuvant effect to improve the efficacy of chemo/radio/immunotherapeutic strategies for cancer treatment.

Right ventricular myocardial oxygen tension is reduced in monocrotaline-induced pulmonary hypertension in the rat and restored by myo-inositol trispyrophosphate

“…We have previously shown that ITPP shifts the oxygen dissociation curve downward, therefore increasing tissue oxygen delivery, increases oxygen delivery to hypoxic tumors 14 , and reduces HIF-1 expression by vascular endothelial cells 15 . This is accompanied by a potent anti-cancer effect in various tumor models in the mouse 14 , 16 . Moreover, we have recently shown that chronic ITPP treatment partially prevents post-myocardial infarction heart failure in the rat model 17 .…”

The Anti-Angiogenesis Mechanism of Geniposide on Rheumatoid Arthrits is Related to the Regulation of PTEN

“…In addition, PI3K is activated by growth factors and angiogenesis inducers, such as vascular endothelial growth factor (VEGF) and angiopoietins, activates Akt or other targets, and induces HIF-1 and VEGF expression to regulate angiogenesis [40,41] . PTEN de cient endothelial cells showing increased excessive angiogenesis have been demonstrated in the vasculogenesis of tumors [42,43] . Akt regulates multiple downstream targets, including nitric oxide synthase (NOS), nuclear factor kappaB (NF-кB), glycogen synthase kinase 3(GSK-3), and Jun N-terminal kinase (JNK).…”

Immunology and Immunotherapy of Endometriosis

“…Moreover, it was shown that NK cell infiltration and its antitumor activity are impaired by the immune checkpoint molecule PD-L1, which is expressed under hypoxic conditions on endothelial cells in the tumor. The normalization of a hypoxic condition reverts immunosuppression into an antitumor immune response [42]. We may thus hypothesize that the same type of mechanism occurs in endometriosis lesions; nevertheless, further investigation is needed.…”