Systemic Blockade of Transforming Growth Factor-β Signaling Augments the Efficacy of Immunogene Therapy

Abstract

Locally produced transforming growth factor-B (TGF-B) promotes tumor-induced immunosuppression and contributes to resistance to immunotherapy. This article explores the potential for increased efficacy when combining immunotherapies with TGF-B suppression using the TGF-B type I receptor kinase inhibitor SM16. Adenovirus expressing IFN-B (Ad.IFN-B) was injected intratumorally once in established s.c. AB12 (mesothelioma) and LKR (lung cancer) tumors or intratracheally in a Kras orthotopic lung tumor model. Mice bearing TC1 (lung cancer) tumors were vaccinated with two injections of adenovirus expressing human papillomavirus-E7 (HPV-E7; Ad.E7). SM16 was administered orally in formulated chow. Tumor growth was assessed and cytokine expression and cell populations were measured in tumors and spleens by real-time PCR and flow cytometry. SM16 potentiated the efficacy of both immunotherapies in each of the models and caused changes in the tumor microenvironment. The combination of SM16 and Ad.IFN-B increased the number of intratumoral leukocytes (including macrophages, natural killer cells, and CD8 + cells) and increased the percentage of T cells expressing the activation marker CD25. SM16 also augmented the antitumor effects of Ad.E7 in the TC1 flank tumor model. The combination did not increase HPV-E7 tetramer-positive CD8 + T cells in the spleens but did induce a marked increase in the tumors. Tumors from SM16-treated mice showed increased mRNA and protein for immunostimulatory cytokines and chemokines, as well as endothelial adhesion molecules, suggesting a mechanism for the increased intratumoral leukocyte trafficking. Blockade of the TGF-B signaling pathway augments the antitumor effects of Ad.IFN-B immune-activating or Ad.E7 vaccination therapy. The addition of TGF-B blocking agents in clinical trials of immunotherapies may increase efficacy.

Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity

“…Taken together, these results demonstrate that SB-431542 can induce potent phenotypic and functional maturation of murine and human DCs. Although we can find several studies of the immunological therapeutic effect of TGFß blocking (39,40), this is the first published study in which a small-molecule inhibitor of the TGFß receptor triggers maturation of DCs.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…It is likely that TGF-b inhibitors will have their most important therapeutic activity in cancer through effects on the TME, particularly, but not only, in neutralizing or reversing immune suppression. Indeed, the combination of TGF-b inhibition together with existing immunotherapies, such as cancer vaccines (Jia et al 2005;Nemunaitis and Murray 2006;Kim et al 2008), adoptive Tcell transfer Wallace et al 2008), chimeric antigen receptor T-cell therapy (Gill and June 2015;Wu et al 2015), and immune checkpoint blockade (Topalian et al 2012;Lipson et al 2013), will likely provide the major basis of their therapeutic usage. Here again, the major players appear to be TGF-b1 and -b2.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…However, another study showed that TGFβ reduces the expression of the adhesion molecule L-Selectin, resulting in impaired neutrophil recruitment to sites of inflammation [86]. Blockage of TGFβ signaling increased the numbers of neutrophils in tumors, which was associated with increased amount of chemokines and cytokines within the tumor, concomitant with increased ICAM-1 expression on endothelial cells [13,90]. The increase in intra-tumor neutrophil number observed following anti-TGFβ signaling therapy can be explained by the ability of TGFβ to inhibit endothelial adhesiveness of neutrophils and neutrophil transmigration in vivo [91].…”