Editors' ChoiceCancer

Tumor influence over immune cells

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Science Translational Medicine  22 Aug 2018:
Vol. 10, Issue 455, eaau8873
DOI: 10.1126/scitranslmed.aau8873


Tumor cell–intrinsic factors, unrelated to antigenicity, control immune cell infiltration and sensitivity to immunotherapy in a mouse model.

Tumors are composed of heterogeneous malignant clones, each with distinct genetic and epigenetic characteristics that influence immune cell infiltration and response to immunotherapy. Certain traits, such as neoantigen burden, antigen processing capability, and interferon-γ responsiveness, contribute to a varied tumor microenvironment within and between tumors. Other factors are less well understood and particularly difficult to study in the context of the complex mixture of transformed cells that form a tumor mass.

In a recent paper, Li et al. report a study in which they used a mouse model of pancreatic ductal adenocarcinoma to investigate the influence of distinct tumor clones on the infiltrating immune cell landscape and on response to immunotherapy. The investigators subcloned tumors from KPC mice (an autochthonous tumor model) to generate tumor lines with identical oncogenic drivers and similar antigenic traits but with distinct patterns of immune cell infiltration. Tumor mixing experiments revealed that low-infiltration tumor clones dominated over high-infiltration clones, which suggested that a secreted factor may be involved in suppressing infiltration. Transcriptomic analysis revealed CXCL1 to be the most differentially expressed chemokine between T cell–high versus T cell–low tumors (increased in the T cell–low tumors). Deletion of CXCL1 rendered immunotherapy-resistant, low T cell–infiltration tumors sensitive to treatment with immunotherapy with an anti-CD40 agonist plus anti–cytotoxic T lymphocyte antigen–4 and anti–programmed cell death 1.

These findings show a dominant role for CXCL1 in controlling immune cell infiltration and responsiveness to immunotherapy, which suggests that CXCL1 and related molecules may be promising therapeutic targets. In addition, the research model of characterizing the tumor microenvironment of subcloned tumor cells may be a valuable template for researchers seeking to understand tumor heterogeneity, immune cell infiltration, and sensitivity to immunotherapy.

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