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

• Published in: Journal of cellular and molecular medicine 2021-04, Vol.25 (7), p.3284-3299
• Main Authors: El Hafny‐Rahbi, Bouchra, Brodaczewska, Klaudia, Collet, Guillaume, Majewska, Aleksandra, Klimkiewicz, Krzysztof, Delalande, Anthony, Grillon, Catherine, Kieda, Claudine
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antitumor activity; Bone marrow; cancer; Cancer therapies; CD45 antigen; CD8 antigen; Cell culture; Chemokines; Cooperation; Cytotoxicity; Endothelial cells; Ethics; Experiments; Helper cells; Hypoxia; immune response; Immunological tolerance; Immunosuppression; Inositol; Life Sciences; Lymphocytes T; Macrophages; Melanoma; microenvironment; Microenvironments; myo‐inositol trispyrophosphate; Original; oxygen partial pressure (pO2); Oxygen tension; PD-1 protein; PD-L1 protein; Phenotypes; PTEN protein; Recruitment; Tensin; Tumor microenvironment; Tumors; vessel normalization
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16399

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.