Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy

• Published in: PloS one 2016-04, Vol.11 (4), p.e0153053-e0153053
• Main Authors: Kodumudi, Krithika N, Siegel, Jessica, Weber, Amy M, Scott, Ellen, Sarnaik, Amod A, Pilon-Thomas, Shari
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animal experimentation; Animals; Antigens; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Biology and Life Sciences; Cancer; Cancer therapies; Care and treatment; Cell survival; Cloning; Colorectal cancer; Deactivation; Delay; Dosage and administration; Female; Health aspects; Immune checkpoint; Immune response; Immunoglobulins; Immunology; Immunoregulation; Inactivation; Infiltration; Interferon; Laboratory animals; Ligands; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Medical prognosis; Medicine and Health Sciences; Melanoma; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Monoclonal antibodies; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; PD-L1 protein; Physiological aspects; Regulators; Research and Analysis Methods; T cell receptors; T cells; Tumor-infiltrating lymphocytes; Tumors; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0153053

Tumor-infiltrating lymphocytes (TIL) has been associated with improved survival in cancer patients. Within the tumor microenvironment, regulatory cells and expression of co-inhibitory immune checkpoint molecules can lead to the inactivation of TIL. Hence, there is a need to develop strategies that disrupt these negative regulators to achieve robust anti-tumor immune responses. We evaluated the blockade of immune checkpoints and their effect on T cell infiltration and function. We examined the ability of TIL to induce tumor-specific immune responses in vitro and in vivo. TIL isolated from tumor bearing mice were tumor-specific and expressed co-inhibitory immune checkpoint molecules. Administration of monoclonal antibodies against immune checkpoints led to a significant delay in tumor growth. However, anti-PD-L1 antibody treated mice had a significant increase in T cell infiltration and IFN-γ production compared to other groups. Adoptive transfer of in vitro expanded TIL from tumors of anti-PD-L1 antibody treated mice led to a significant delay in tumor growth. Blockade of co-inhibitory immune checkpoints could be an effective strategy to improve TIL infiltration and function.