GK-1 effectively reduces angiogenesis and prevents T cell exhaustion in a breast cancer murine experimental model

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 11; pp. 3825 - 3838
• Main Authors: Hernández-Aceves, Juan A., Cervantes-Torres, Jacquelynne, Torres-García, Diana, Zuñiga-Flores, Francisco J., Patiño-Chávez, Osiris J., Peña Agudelo, Jorge A., Aguayo-Flores, José Eduardo, Garfias, Yonathan, Montero-León, Laura, Romero-Romero, Laura, Pérez-Torres, Armando, Fragoso, Gladis, Sciutto, Edda
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2023; Springer Nature B.V
• Subjects: Angiogenesis; Angiopoietin; Antitumor activity; Breast cancer; Cancer immunotherapy; Cancer Research; CD8 antigen; Cytotoxicity; Endothelin 1; Immunology; Leukemoid reaction; Lymph nodes; Lymphocytes T; Malignancy; Medicine; Medicine & Public Health; Metastases; Metastasis; Oncology; PD-1 protein; SDF-1 protein; Tumor cells; Tumor-infiltrating lymphocytes; Vascular endothelial growth factor; Vascular endothelial growth factor C; γ-Interferon; T cell exhaustion; Angiogenesis; GK-1; Breast cancer; 4T1-model; Immunotherapy
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-023-03538-9

Breast cancer is the leading malignancy in women worldwide, both in terms of incidence and mortality. Triple-negative breast cancer (TNBC) is the type with the worst clinical outcomes and with fewer therapeutic options than other types of breast cancer. GK-1 is a peptide that in the experimental model of the metastatic 4T1 breast cancer has demonstrated anti-tumor and anti-metastatic properties. Herein, GK-1 (5 mg/kg, i.v.) weekly administrated not only decreases tumor growth and the number of lung macro-metastases but also lung and lymph nodes micro-metastases. Histological analysis reveals that GK-1 reduced 57% of the intra-tumor vascular areas, diminished the leukemoid reaction's progression, and the spleens' weight and length. A significant reduction in VEGF-C, SDF-1, angiopoietin-2, and endothelin-1 angiogenic factors was induced. Moreover, GK-1 prevents T cell exhaustion in the tumor-infiltrating lymphocytes (TILs) decreasing PD-1 expression. It also increased IFN-γ and granzyme-B expression and the cytotoxic activity of CD8
+
TILs cells against tumor cells. All these features were found to be associated with a better antitumor response and prognosis. Altogether, these results reinforce the potential of GK-1 to improve the clinical outcome of triple-negative breast cancer immunotherapy. Translation research is ongoing towards its evaluation in humans.