Journal Article

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

Kinzler, Kenneth W., Papadopoulos, Nickolas, Zhou, Shibin, Liu, Qiang, Vogelstein, Bert, Skora, Andrew D., Kim, KiBem, Li, Zhaobo, Tam, Ada J., Blosser, Richard L., Diaz, Luis A.

2014

Overview

Impressive responses have been observed in patients treated with checkpoint inhibitory anti–programmed cell death-1 (PD-1) or anti–cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti–PD-1 and anti–CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.

• Publisher: National Academy of Sciences
• Subject: Animals / Antibodies / Antibodies, Monoclonal - administration & dosage / Apoptosis / Azacitidine - administration & dosage / Benzamides - administration & dosage / Biological Sciences / Cancer / Cell Line, Tumor / Cellular immunity / Colorectal Neoplasms - immunology / Colorectal Neoplasms - secondary / Colorectal Neoplasms - therapy / Combined Modality Therapy / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - immunology / Cytotoxicity / drugs / Epigenesis, Genetic - drug effects / Epigenetics / Female / Histone Deacetylase Inhibitors - administration & dosage / Humans / Immunology and Inflammation / Immunotherapy / Immunotherapy - methods / Lymphocytes / Mammary Neoplasms, Experimental - immunology / Mammary Neoplasms, Experimental - secondary / Mammary Neoplasms, Experimental - therapy / Medical treatment / Metastasis / Mice / Mice, Inbred BALB C / Myeloid cells / Myeloid Cells - drug effects / Myeloid Cells - immunology / Neoplasm Metastasis - genetics / Neoplasm Metastasis - immunology / Neoplasm Metastasis - therapy / neoplasms / patients / phosphatidylinositol 3-kinase / Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Polyclonal antibodies / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - immunology / Pyridines - administration & dosage / Rodents / suppressor cells / T lymphocytes / Tumor cell line / Tumors