Novel Targets for Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our laboratory has previously identified the embryonic transcription factor brachyury as a tumor antigen, and a driver of cancer cell plasticity. Brachyury is expressed in various cancer types, including in small cell lung cancer, triple negative breast cancer, lung cancer, and the rare tumor type chordoma, while being almost undetectable in the majority of adult normal tissues. To date, several therapeutic cancer vaccines targeting brachyury have been developed by our laboratory in collaboration with the private sector. Recently, a phase I clinical study of a modified vaccinia Ankara (MVA) vector vaccine encoding for brachyury and three costimulatory molecules, TRICOM, demonstrated that the intravenous administration of MVA-brachyury-TRICOM is safe and tolerable in patients with advanced solid tumors, with some evidence of clinical responses in chordoma patients, and development of brachyury-specific T cells. The study of brachyury as a tumor antigen and its role as a driver of cancer cell plasticity led us to also demonstrate a link between the acquisition of mesenchymal features by carcinoma cells and the acquisition of mechanisms of resistance to lysis by immune effector cells. Following these observations, we investigated approaches to improve tumor susceptibility to immune attack via modulation of tumor phenotype. One of the drivers of cancer cell plasticity is the transforming growth factor beta (TGF-beta). Our laboratory showed that the combined use of a CXCR1/2 inhibitor with a bifunctional agent that simultaneously blocks PD-L1 and 'traps' soluble TGF-beta at the site of the tumor, termed bintrafusp alfa, results in more effective anti-tumor control, compared to each monotherapy. We showed that simultaneous inhibition of CXCR1/2, TGF-beta, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly enhance the expression of tumor epithelial markers while reducing infiltration with suppressive G-MDSCs, enhancing tumor infiltration and activation of T-cells, and leading to improved anti-tumor activity. In addition to inducing cancer cell plasticity, TGF-beta is a regulator of the extracellular matrix by stimulating the production of collagens by cancer-associated fibroblasts, and by promoting the synthesis of enzymatic proteins that are involved in the crosslinking or degradation of collagens. In the tumor microenvironment, collagens provide a physical barrier to immune infiltration, while also acting as ligand for inhibitory receptors in immune cells. In a recent study, we investigated whether blockade of collagen signals via the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-beta and programmed cell death ligand 1 (PD-L1) could afford better tumor control. We showed that this combined approach is able to remodel collagens, enhance tumor infiltration and activation of CD8 T cells, and repolarize suppressive M2 macrophages leading to high cure rates and long-term tumor-specific protection in murine models of colon and breast cancer. Altogether, our results provide rationale for the use of strategies that simultaneously block IL-8 signaling, neutralize TGF-beta in the tumor microenvironment, inhibit PD-L1, and block negative immune signaling derived from the collagenous component of the extracellular matrix.