Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade
| Autor: | Rita Greco, Dmitri Wiederschain, Frank Sun, Jack Pollard, Alexei Protopopov, Sharad K. Sharma, Christopher Winter, Annie Best, Gary Shapiro, Andrew Hebert, Mikhail Levit, Lily Pao, Julie Jaworski, Hongjing Qu, Joachim Theilhaber, Hui Qu, Keith Bahjat, Natalia Malkova, Richard C. Gregory |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
tgfβ medicine.medical_treatment Immunology Programmed Cell Death 1 Receptor Context (language use) T cell response 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine Immune Tolerance Immunology and Allergy Animals Humans tumor microenvironment Combination immunotherapy RC254-282 Original Research Immunosuppression Therapy Tumor microenvironment pd1 blockade business.industry Antibodies Monoclonal Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunosuppression RC581-607 030104 developmental biology Cytokine Oncology 030220 oncology & carcinogenesis combination immunotherapy Cancer research Pd 1 blockade t cell response Immunologic diseases. Allergy business Research Article |
| Zdroj: | OncoImmunology, Vol 9, Iss 1 (2020) Oncoimmunology article-version (VoR) Version of Record |
| Popis: | 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). |
| Databáze: | OpenAIRE |
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