TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of 8%. This is mainly attributed to the late stage of presentation, as well as widespread resistance to conventional therapy. In addition, PDAC tumors are largely nonimmunogenic, and most patients have displayed incomplete responses to cancer immunotherapies. Our group has previously identified TGFb as a crucial repressor of antitumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes. However, pharmacologic inhibition of TGFb signaling has had limited efficacy in clinical trials, failing to promote a significant antitumor immune response. Hence, in this work, we extend our analysis to identify and circumvent the mechanisms of resistance to TGFb signal inhibition in PDAC. Consistent with our previous observations, adoptive transfer of TGFb-insensitive CD8 þ T cells led to the near complete regression of neoplastic disease in vivo. However, we demonstrate that this cannot be recapitulated via global reduction in TGFb signaling, through either genetic ablation or pharmacologic inhibition of TGFBR1. In fact, tumors with TGFb signal inhibition displayed increased PD-L1 expression and had no observable change in antitumor immunity. Using genetic models of advanced PDAC, we then determined that concomitant inhibition of both TGFb and PD-L1 receptors led to a reduction in the neoplastic phenotype, improving survival and reducing disease-associated morbidity in vivo. Combined, these data strongly suggest that TGFb and PD-L1 pathway inhibitors may synergize in PDAC, and this approach warrants clinical consideration. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Combined Inhibition of TGF-β Signaling and the PD-L1 Immune Checkpoint Is Differentially Effective in Tumor Models

“…However, it is unclear whether lack of response to PD-L1 checkpoint blockade is also correlated with active TGF-β signaling in other patients of different tumor types. Furthermore, even though the combination of TGF-β blockade and checkpoint inhibitors has been demonstrated in multiple preclinical studies, their therapeutic efficacy varies across a range of syngeneic tumors [27,45,46,63,64,65]. Together, our studies indicate that adequate immune phenotyping of the various tumor models is critical for both rational model selection and data interpretation.…”

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

“…We cannot exclude that the effects of TGFβ-neutralization span beyond the modulation of CAF phenotypes and functions. Given that TGFβ is known to restrict T cell proliferation through the reduction of IL-2 production, as well as downregulate expression of certain cytotoxic effector mediators 96 , it is in fact conceivable that TGFβ-neutralization may act both on stromal cells to promote T cell infiltration, and directly on tumorinfiltrating lymphocytes to enhance their activity 97 . Nevertheless, our data demonstrate that limiting TGFβ bioavailability elicits the formation of an immune-permissive microenvironment, in line with recent reports illustrating that TGFβ targeting through different methodologies allows immunological control of tumor growth in combination with checkpoint blockade therapy 35,53,98 .…”

DNT Cell-based Immunotherapy: Progress and Applications

“…In addition, TGF-β also inhibited the activity of CD4+ and CD8+ T cells, thereby facilitating the escape of cancer cells from T cell killing and the generation of a tumor microenvironment that blocks T cell action. Therefore, DNTs may be considered in combination with TGF-β inhibitors; however, whether this combination enhances DNT cytotoxicity remains to be further studied [105,106].…”