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Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.

ABSTRACT: The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8⁺ T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics. Here, we investigated the effect of TGF-β blockade on the antitumor efficacy of Reo&CD3-bsAb therapy in the preclinical pancreatic KPC3 and colon MC38 tumor models, where TGF-β signaling is active. TGF-β blockade impaired tumor growth in both KPC3 and MC38 tumors. Furthermore, TGF-β blockade did not affect reovirus replication in both models and significantly enhanced the Reo-induced T-cell influx in MC38 colon tumors. Reo administration decreased TGF-β signaling in MC38 tumors but instead increased TGF-β activity in KPC3 tumors, resulting in the accumulation of α-smooth muscle actin (αSMA⁺) fibroblasts. In KPC3 tumors, TGF-β blockade antagonized the antitumor effect of Reo&CD3-bsAb therapy, even though T-cell influx and activity were not impaired. Moreover, genetic loss of TGF-β signaling in CD8⁺ T cells had no effect on therapeutic responses. In contrast, TGF-β blockade significantly improved therapeutic efficacy of Reo&CD3-bsAb in mice bearing MC38 colon tumors, resulting in a 100% complete response. Further understanding of the factors that determine this intertumor dichotomy is required before TGF-β inhibition can be exploited as part of viroimmunotherapeutic combination strategies to improve their clinical benefit.

Significance

Blockade of the pleiotropic molecule TGF-β can both improve and impair the efficacy of viro-immunotherapy, depending on the tumor model. While TGF-β blockade antagonized Reo&CD3-bsAb combination therapy in the KPC3 model for pancreatic cancer, it resulted in 100% complete responses in the MC38 colon model. Understanding factors underlying this contrast is required to guide therapeutic application.

SUBMITTER: Groeneveldt C

PROVIDER: S-EPMC9973387 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.

Groeneveldt Christianne C van Ginkel Jurriaan Q JQ Kinderman Priscilla P Sluijter Marjolein M Griffioen Lisa L Labrie Camilla C van den Wollenberg Diana J M DJM Hoeben Rob C RC van der Burg Sjoerd H SH Ten Dijke Peter P Hawinkels Lukas J A C LJAC van Hall Thorbald T van Montfoort Nadine N

Cancer research communications 20230223 2

The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8<sup>+</sup> T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteri ...[more]

PMID: 36860656

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Dataset Information

Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.

Significance

Publications

Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.

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