Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade

Oncoimmunology. 2020 Sep 13;9(1):1811605. doi: 10.1080/2162402X.2020.1811605.


TGFβ is a pleiotropic cytokine that may have both tumor inhibiting and tumor promoting properties, depending on tissue and cellular context. Emerging data support a role for TGFβ in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFβ neutralizing antibody, inhibits all active isoforms of human and murine TGFβ, blocks TGFβ-mediated pSMAD signaling, and TGFβ-mediated suppression of T cells and NK cells. In vitro, SAR439459 synergized with anti-PD1 to enhance T cell responsiveness. In syngeneic tumor models, SAR439459 treatment impaired tumor growth, while the combination of SAR439459 with anti-PD-1 resulted in complete tumor regression and a prolonged antitumor immunity. Mechanistically, we found that TGFβ inhibition with PD-1 blockade augmented intratumoral CD8+ T cell proliferation, reduced exhaustion, evoked proinflammatory cytokines, and promoted tumor-specific CD8+ T cell responses. Together, these data support the hypothesis that TGFβ neutralization using SAR439459 synergizes with PD-1 blockade to promote antitumor immunity and formed the basis for the ongoing clinical investigation of SAR439459 in patients with cancer (NCT03192345).

Keywords: PD1 blockade; T cell response; TGFβ; Tumor microenvironment; combination immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Cell Line, Tumor
  • Humans
  • Immune Tolerance
  • Immunosuppression Therapy*
  • Mice
  • Programmed Cell Death 1 Receptor*


  • Antibodies, Monoclonal
  • Programmed Cell Death 1 Receptor

Associated data