Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to imunotherapy Journal Article
| Authors: | Li, J.; Byrne, K. T.; Yan, F.; Yamazoe, T.; Chen, Z.; Baslan, T.; Richman, L. P.; Lin, J. H.; Sun, Y. H.; Rech, A. J.; Balli, D.; Hay, C. A.; Sela, Y.; Merrell, A. J.; Liudahl, S. M.; Gordon, N.; Norgard, R. J.; Yuan, S.; Yu, S.; Chao, T.; Ye, S.; Eisinger-Mathason, T. S. K.; Faryabi, R. B.; Tobias, J. W.; Lowe, S. W.; Coussens, L. M.; Wherry, E. J.; Vonderheide, R. H.; Stanger, B. Z. |
| Article Title: | Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to imunotherapy |
| 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. Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors. © 2018 |
| Journal Title: | Immunity |
| Volume: | 49 |
| Issue: | 1 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2018-07-17 |
| Start Page: | 178 |
| End Page: | 193.e7 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2018.06.006 |
| PROVIDER: | scopus |
| PUBMED: | 29958801 |
| PMCID: | PMC6707727 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
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