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Immunity. 2018 Jul 17;49(1):178-193.e7. doi: 10.1016/j.immuni.2018.06.006. Epub 2018 Jun 26.

Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy.

Author information

1
Abramson Family Cancer Research Institute, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
2
Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA. Electronic address: byrnek@upenn.edu.
3
Institute for Immunology, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
4
Cancer Biology and Genetics Program, Sloan-Kettering Institute, NY 10065, USA.
5
Center for RNA Biology, Department of Biochemistry and Biophysics, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
6
Abramson Family Cancer Research Institute, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
7
Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
8
Department of Cell, Developmental and Cancer Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
9
Abramson Family Cancer Research Institute, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
10
Penn Genomic Analysis Core, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
11
Cancer Biology and Genetics Program, Sloan-Kettering Institute, NY 10065, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, 415 East 68(th) Street New York, NY 10065, USA.
12
Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA.
13
Abramson Family Cancer Research Institute, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA. Electronic address: rhv@upenn.edu.
14
Abramson Family Cancer Research Institute, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USA. Electronic address: bstanger@upenn.edu.

Abstract

The biological and functional heterogeneity between tumors-both across and within cancer types-poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.

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