TGF-β: A novel predictor and target for anti-PD-1/PD-L1 therapy

Abstract

Transforming growth factor-β (TGF-β) signaling regulates multiple physiological processes, such as cell proliferation, differentiation, immune homeostasis, and wound healing. Besides, TGF-β plays a vital role in diseases, including cancer. Accumulating evidence indicates that TGF-β controls the composition and behavior of immune components in the tumor microenvironment (TME). Advanced cancers leverage TGF-β to reshape the TME and escape immune surveillance. TGF-β-mediated immune evasion is an unfavorable factor for cancer immunotherapy, especially immune checkpoint inhibitors (ICI). Numerous preclinical and clinical studies have demonstrated that hyperactive TGF-β signaling is closely associated with ICI resistance. It has been validated that TGF-β blockade synergizes with ICI and overcomes treatment resistance. TGF-β-targeted therapies, including trap and bispecific antibodies, have shown immense potential for cancer immunotherapy. In this review, we summarized the predictive value of TGF-β signaling and the prospects of TGF-β-targeted therapies for cancer immunotherapy.

Comprehensive analysis of the immune implication of EPHX4 gene in laryngeal squamous cell carcinoma

“…Nowadays, increasing evidence verified that immune checkpoint blockade plays a vital role in the treatment for cancer therapy, especially for advanced cancers. 18 To better understand the underlying molecular and biological function of EPHX4 protein, we performed TISIDB analysis to specify the relationship between EPHX4 and immunomodulator in HNSCC. Most of the immune gene integrated into prognostic signatures involved in the regulation of the activity and proliferation of T-cells, highlighting the importance of T-cell-mediated immunity in HNSCC.…”

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors

“…The other modification in AdAPT-001 is deletion of the E1B-19K gene—a Bcl-2 adenoviral homolog that potently inhibits apoptosis [ 15 ]—and its replacement with a Transforming Growth Factor-beta (TGF-β) ligand “trap”; this trap is a TGFβ receptor ectodomain-IgG Fc fusion protein, which binds to and neutralizes the potently immunosuppressive and fibrosis-inducing cytokine, TGF-β [ 9 ].…”

“…Tumors with an immune-devoid phenotype are known as “cold” and these are generally unresponsive to checkpoint inhibitors. Of interest, then, is the combination of AdAPT-001 with checkpoint inhibitors, as the combination of viral infection and the expression of the TGF-β trap transgene may induce lymphocytic infiltration and prime for checkpoint inhibition efficacy since high levels of the TGF-β cytokine are associated with poorly T-cell infiltrated, “cold” tumors, which are resistant to immunotherapy [ 15 ]. That said, cancer is a systemic disease and for a localized therapy like AdAPT-001 to systemically treat and control cancer as a single agent, especially in the setting of gross metastatic disease, requires the induction of an abscopal effect in which tumor-reactive T cells within the injected tumor migrate to and eliminate noninjected or “secondary” tumors [ 16 ].…”

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-β receptor I inhibitor, in patients with advanced solid tumors

“…Emerging evidence indicates that TGF-β signaling promotes resistance to therapies (chemotherapy, targeted therapy, and immunotherapy) [ 6 ]. This pathway may be leveraged to reshape the immunosuppressive TME and define a bypass mechanism for immune checkpoint inhibitor therapy [ 7 , 8 ]. Preclinical and clinical findings show that TGF-β blockade improves the anti-PD-1/L1 response [ 9 , 10 ].…”