Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma

Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8 T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngene...

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Podrobná bibliografie
Vydáno v:	Immunity (Cambridge, Mass.) Ročník 53; číslo 3; s. 564
Hlavní autoři:	Effern, Maike, Glodde, Nicole, Braun, Matthias, Liebing, Jana, Boll, Helena N, Yong, Michelle, Bawden, Emma, Hinze, Daniel, van den Boorn-Konijnenberg, Debby, Daoud, Mila, Aymans, Pia, Landsberg, Jennifer, Smyth, Mark J, Flatz, Lukas, Tüting, Thomas, Bald, Tobias, Gebhardt, Thomas, Hölzel, Michael
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 15.09.2020
Témata:	Adoptive Transfer - methods Animals CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - transplantation Cell Line, Tumor Cell- and Tissue-Based Therapy - methods Epitopes, T-Lymphocyte - genetics Epitopes, T-Lymphocyte - immunology Gene Knockout Techniques Immune Checkpoint Inhibitors - pharmacology Melanoma - immunology Melanoma - therapy Mice Mice, Inbred C57BL Myeloid Cells - cytology Myeloid Cells - immunology Tumor Escape - immunology Tumor Microenvironment - immunology adoptive T cell therapy antigen loss phenotype switching PD-L1 dedifferentiation melanoma plasticity immune escape epitope resistance
ISSN:	1097-4180, 1097-4180
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Popis
Shrnutí:	Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8 T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8 T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4 (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8 T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4 , promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4 antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2020.07.007