1. Targeting Immune Checkpoints in Esophageal Cancer: A High Mutational Load Tumor 
Rajeev Dhupar, MD, Lauren Van Der Kraak, PhD, Arjun Pennathur, MD, Matthew J. Schuchert, MD, Katie S. Nason, MD, James D. Luketich, MD, Michael T. Lotze, MD 
The Annals of Thoracic Surgery 
Volume 103, Issue 4, Pages (April 2017)
DOI: /j.athoracsur
Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

2. Fig 1
Normal activation and inactivation of immune cells. (Upper panel) A CD8+ T-cell can be activated after interaction with an antigen-presenting cell, after which the T-cell can kill cancer cells. (Lower panel) However, a natural “braking” system (ie, negative feedback) to prevent an overwhelming immune response occurs when checkpoint proteins inactivate these T-cells. (CD8+ = cluster of differentiation 8; MHC = major histocompatibility complex; TCR = T-cell receptor.)
The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur )
Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

3. Fig 2
Cancer cells “hijacking” checkpoint proteins to evade the immune system. (Upper panel) Some cancer cells express checkpoint proteins, which inactivate T-cells and allow the cancer cells to evade the immune system and escape death. (Lower panel) However, checkpoint inhibitor proteins can block this method of evasion by the cancer cells, thereby allowing the immune system to kill cancer cells. (CD8+ = cluster of differentiation 8.)
The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur )
Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

4. Fig 3
Literature search performed. Papers examined were restricted to those in English and those with either adenocarcinoma or squamous carcinoma of the esophagus. (B7-DC = B7-dendritic cell; B7-H1 = B7-homolog 1; CTLA-4 = cytotoxic T-lymphocyte associated protein 4; DC = dendritic cell; IL-2 = interleukin-2; LAG3 = lymphocyte activation gene 3; PD-L1 = programmed cell death ligand 1; PD-1 = programmed cell death protein 1; TIGIT = T-cell immunoglobulin and ITIM domain; TIM3 = T-cell immunoglobulin mucin 3.)
The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur )
Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions

5. Fig 4
Proposed key pathways that effect PD-L1/2 expression in esophageal adenocarcinoma. In esophageal cancer, expression of PD-L1 and PD-L2 is likely modulated by numerous environmental factors (chemotherapy, radiation, or other inflammatory states) that are currently not well defined. Stress-responsive receptors and transcription factors (such as interferon regulatory factors/toll-like receptors) and adaption mechanisms (such as autophagy) contribute to tumor survival by enhancing surface expression of checkpoint inhibitors. Understanding these interactions will be critical to determine how to improve treatments that allow unleashing of the immune system to overcome tumor defense mechanisms such as PD-L1/2 expression, expression of immunosuppressive cytokines, and protective autophagy. (CD4+ = cluster of differentiation 4; CD8+ = cluster of differentiation 8; CD 80 = cluster of differentiation 80; CTLA-4 = cytotoxic T-lymphocyte associated protein 4; DC = dendritic cell; HMGB1 = high mobility group box 1; IFN = interferon; IL = interleukin; IRF = interferon regulatory factor; PD-L1 = programmed cell death ligand 1; PD-L2 = programmed cell death ligand 2; PD-1 = programmed cell death protein 1; RAGE = receptor for advanced glycation end products; TGF = transforming growth factor; TLR4 = toll-like receptor 4; Treg = regulatory T-cell.)
The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur )
Copyright © 2017 The Society of Thoracic Surgeons Terms and Conditions