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

SIMPLE SUMMARY: Upregulation of transforming growth factor-beta (TGF-β) signaling in melanoma contributes to the formation of immune-suppressive tumoral environments and is associated with poor response to immunotherapeutics, including anti-programmed death-1 (PD-1) therapy. Our study aimed to investigate the immunotherapeutic potential of a novel next-generation TGF-β2 antisense oligonucleotide (ngTASO) in combination with anti-PD-1 therapy using a melanoma-bearing human immune system mouse model. Our findings confirm that blockade of TGF-β signaling by ngTASO improves the T cell-mediated antitumor potential of anti-PD-1 therapy via facilitating intratumoral infiltration of CD8+ cytotoxic lymphocytes and their activation. These results suggest that ngTASO is a promising combination strategy with anti-PD-1 therapy for the treatment of immune-excluded melanoma. ABSTRACT: 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.