Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes

Bai, Xue‐Feng; Liu, Jinqing; Ou, Li; Zheng, Pan; Liu, Yang

doi:10.1172/jci17656

Cited by 92 publications

(65 citation statements)

References 40 publications

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“…Postulated underlying contributing mechanisms of resistance include: development of functional tolerance (11), antigenic ignorance (low levels of Ag expression) (12), down-regulation of Ag presentation associated molecules (13), tolerance induction to target Ag (14), and/or effector cell exhaustion (15). Tumors can also qualitatively or quantitatively alter their Ag expression by mutation/down-regulation of Ag epitopes leading to regulation of peptide:MHC interaction and TCR binding (16) or via complete Ag-loss (17). …”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction

et al. 2011

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Durable responses in metastatic melanoma patients remain generally difficult to achieve. Adoptive cell therapy with ex vivo engineered lymphocytes expressing high affinity T cell receptors TCRα/β for the melanoma antigen MART-127-35/HLA A*0201 (recognized by F5 cytotoxic T lymphocytes [F5 CTLs]) has been found to benefit certain patients. However, many other patients are inherently unresponsive and/or relapse for unknown reasons. To analyze the basis for the acquired-resistance and strategies to reverse it, we established F5 CTLresistant (R) human melanoma clones from relatively sensitive parental lines under selective F5 CTL pressure. Surface MART-127-35/HLA-A*0201 in these clones was unaltered and F5 CTLs recognized and interacted with them similarly to the parental lines. Nevertheless, the R clones were resistant to F5 CTL killing, exhibited hyperactivation of the NF-κB survival pathway, and overexpression of the anti-apoptotic genes Bcl-2, Bcl-xL and Mcl-1. Sensitivity to F5 CTL-killing could be increased by pharmacological inhibition of the NF-κB pathway, Bcl-2 family members, or the proteasome, the latter of which reduced NF-κB activity and diminished anti-apoptotic gene expression. Specific gene-silencing (by siRNA) confirmed the protective role of anti-apoptotic factors by reversing R clone resistance. Together, our findings suggest that long-term immunotherapy may impose a selection for the development of resistant cells that are unresponsive to highly avid and specific melanoma-reactive CTLs, despite maintaining expression of functional peptide:MHC complexes, due to activation of anti-apoptotic signaling pathways. Though unresponsive to CTL, our results argue that resistant cells can be re-sensitized to immunotherapy with co-administration of targeted inhibitors to anti-apoptotic survival pathways.

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Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction

et al. 2011

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“…The extent of antigen loss in tumor cells are comparable between this study and earlier studies using transgenic T cells specific for unmutated tumor antigen P1A (13). The similarity suggests that immune evasion is an obstacle not only for therapy based on unmutated tumor antigens but also for neoantigens.…”

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confidence: 85%

Neoantigen: A Long March toward Cancer Immunotherapy

Liu

2016

Clinical Cancer Research

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“…For instance, mutations in antigenic epitopes, or antigenic drift, enable the tumor to evade host immunity. 23 These antigen presentation machinery deficiencies may be reversed by treatment with interferon gamma (IFN-g). 24 Soluble and exosomal NKG2D ligands Another way that tumors can evade immune recognition is through the shedding of NKG2D ligands, including major histocompatibility complex class I-related molecules A and B (MICA and MICB) and UL16-binding proteins.…”

Section: Molecular Mechanisms Of Immune Evasion By Tumorsmentioning

confidence: 99%

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

et al. 2015

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Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes

Cited by 92 publications

References 40 publications

Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction

Molecular Mechanism of MART-1+/A*0201+ Human Melanoma Resistance to Specific CTL-Killing Despite Functional Tumor–CTL Interaction

Neoantigen: A Long March toward Cancer Immunotherapy

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

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