Noncanonical TGFβ Pathway Relieves the Blockade of IL1β/TGFβ-Mediated Crosstalk between Tumor and Stroma: TGFBR1 and TAK1 Inhibition in Colorectal Cancer

Abstract

Purpose: The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment.Experimental Design: A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblasts' activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor-stroma interaction. Finally, we tested, in vivo, the blockade of the tumor-stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin.Results: IL1b/TGFb1 are the triggers for fibroblasts' recruitment and conversion into carcinoma-associated fibroblasts (CAF) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumor cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralizing IL1b antibody and a TGFBR1 inhibitor is relieved by the TAK1-mediated activation of the noncanonical TGFb pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumor cells. TAK1 plus TGFBR1 inhibition blocks IL1b/TGFb1mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumor cells became more sensitive to chemotherapy. In vivo, the combination of a TAK1 inhibitor plus TGFBR1 inhibitor reduced the metastatic capacity of tumor cells and the recruitment of fibroblasts.Conclusions: Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.

The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

“…In any case, we must be cautious in this regard since it has been shown that the use of JAK inhibitors to attenuate the pro-inflammatory response has increased the proportion of myofibroblasts, with the consequent increase in extracellular matrix deposits, which end up hindering the access of chemotherapy into the tumor [ 43 , 44 ]. This fact would support the strategy of combining an anti-iCAF treatment together with modulation of the action of TGFβ1, in a similar way to what our group published a few years ago by combining a TAK1 inhibitor in combination with Galunisertib [ 41 ].…”

“…The protumoral or antitumor role of each of these subsets described is not clear. Both, IL1β and TGFβ1, along with some more soluble factors, have been described to be molecules that mediate the crosstalk between tumor cells and fibroblasts and are responsible for the activation state of the latter [ 22 , 41 ]. However, different ligands will induce different CAF subsets.…”

Comprehensive Analysis of Key Genes and Regulatory Elements in Osteosarcoma Affected by Bone Matrix Mineral With Prognostic Values

“…Inhibition of TGFBR1 can block the activation of fibroblasts mediated via IL1B/TGFB1 and reduce the secretion of pro-inflammatory cytokines in colorectal cancer, which would make the cancer cells more sensitive to chemotherapy. Moreover, TGFBR1 inhibitor could reduce the metastasis ability of tumor cells in vivo (Guillen Diaz-Maroto et al, 2019). It is also reported that in lung cancer TGFBR1 may be a target of tumor suppressor genes (Gao et al, 2019).…”

IL-2 and Anti-TGF-β Promote NK Cell Reconstitution and Anti-tumor Effects after Syngeneic Hematopoietic Stem Cell Transplantation

“…Alternatively, there are pre-clinical and clinical evidence for the promising synergistic potential of combining immunotherapy with chemotherapy that results in an improvement of the anti-tumor response in multiple cancers, such as breast cancer, metastatic melanoma, metastatic colorectal cancer, acute myeloid leukemia or renal cell carcinoma [60][61][62][63][64]. Similarly, the inhibition of the TGF-β signaling has shown to increase the chemotherapeutic effect in many types of cancers as well [65][66][67][68]. Taking into consideration these studies and our results, one could speculate that the IL-2/TGF-β blockade immunotherapy could also augment the chemotherapy-based anti-tumor responses outside of use in HSCT.…”