Next-Generation Antisense Oligonucleotide of TGF-β2 Enhances T Cell-Mediated Anticancer Efficacy of Anti-PD-1 Therapy in a Humanized Mouse Model of Immune-Excluded Melanoma

• Published in: Cancers 2022-10, Vol.14 (21), p.5220
• Main Authors: Lee, Hong Kyu, Kim, Cho-Won, Ahn, Dohee, Go, Ryeo-Eun, Choi, Youngdong, Choi, Kyung-Chul
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Antisense oligonucleotides; Antisense therapy; Apoptosis; Care and treatment; CD8 antigen; Cell activation; Cloning; Cytotoxicity; FDA approval; Gene expression; Granzyme B; Health aspects; Immune system; Immunoregulation; Immunotherapy; Infiltration; Laboratory animals; Lung cancer; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Methods; Oligonucleotides; PD-1 protein; PD-L1 protein; Peripheral blood; Phenotypes; Skin cancer; T cell receptors; T cells; Therapeutic applications; Transforming growth factor-b; Transforming growth factor-b1; Transforming growth factors; Tumors; β-Catenin
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14215220

Anti-programmed death-1 (PD-1) immunotherapy is one of the most promising therapeutic interventions for treating various tumors, including lung cancer, bladder cancer, and melanoma. However, only a subset of patients responds to anti-PD-1 therapy due to complicated immune regulation in tumors and the evolution of resistance. In the current study, we investigate the potential of a novel transforming growth factor-beta2 (TGF-β2) antisense oligonucleotide (ngTASO), as a combination therapy with an anti-PD-1 antibody in melanoma. This study was conducted in a melanoma-bearing human immune system mouse model that recapitulates immune-excluded phenotypes. We observed that the TGF-β2 blockade by ngTASO in combination with PD-1 inhibition downregulated the tumor intrinsic β-catenin, facilitated the infiltration of CD8+ cytotoxic lymphocytes (CTLs) in the tumor, and finally, enhanced the antitumor immune potentials and tumor growth delays. Blockade of TGF-β2 combined with PD-1 inhibition also resulted in downregulating the ratio of regulatory T cells to CTLs in the peripheral blood and tumor, resulting in increased granzyme B expression. In addition, co-treatment of ngTASO and anti-PD-1 augmented the PD-L1 expression in tumors, which is associated with an improved response to anti-PD-1 immunotherapy. These results indicate that the combination of ngTASO and anti-PD-1 exerts an enhanced T cell-mediated antitumor immune potential. Hence, co-inhibition of TGF-β2 and PD-1 is a potentially promising immunotherapeutic strategy for immune-excluded melanoma.