In the inducible oncogenic KRAS mouse model of PDAC, Gulhati et al. showed that high levels of immunosuppressive myeloid cells contributed to T cell dysfunction and checkpoint blockade resistance. Agonist 4-1BB and antagonist LAG3 (alone or in combination) increased antitumor immunity and survival. This was associated with increased antitumor T cells, more clonal and diverse T cells, reduced number and function of immunosuppressive myeloid cells, and increased antigen presentation by myeloid cells. The addition of a CXCR1/2 inhibitor targeting MDSCs resulted in durable complete responses and resistance to rechallenge. Similar profiles were observed in data from patients with PDAC.
Contributed by Lauren Hitchings
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.
Author Info: (1) Department of Medical Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA. Department of Gastrointestinal Medical Oncology, Division of Cancer
Author Info: (1) Department of Medical Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA. Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. (13) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Syntrix Pharmaceuticals, Auburn, WA, USA. (17) Syntrix Pharmaceuticals, Auburn, WA, USA. (18) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Biostatistics, Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA. (23) Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. yaw@iu.edu. Brown Center for Immunotherapy, Indiana University School of Medicine, Indianapolis, IN, USA. yaw@iu.edu. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. yaw@iu.edu. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. yaw@iu.edu. Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA. yaw@iu.edu. (25) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. rdepinho@mdanderson.org.
