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Tumor immune landscape paintings from the CyTOF period

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Science Immunology  02 Jun 2017:
Vol. 2, Issue 12, eaan8156
DOI: 10.1126/sciimmunol.aan8156

Abstract

Early lung cancer patients harbor cancer-permissive innate immunity in the tumor microenvironment.

Despite the remarkable success of anti–PD-1 antibody treatment in prolonging the life of patients with advanced lung cancers, most metastatic cancers do not effectively respond to checkpoint blockade therapy. Consequently, there is considerable interest in applying immunotherapy to patients before metastatic disease occurs. Rational development of premetastatic cancer immunotherapy requires understanding why early immune responses fail to stop disease progression, as well as identification of relevant target cells and molecules in the early tumor microenvironment.

Working from the premise that innate immune cells, including antigen-presenting cells, are key to shaping tumor-specific T cell responses, Lavin et al. undertook a comprehensive analysis of myeloid and lymphoid cells within tumors, adjacent normal tissue, and blood obtained from 32 premetastatic lung cancer patients. The principal methodology was cytometry by time of flight (CyTOF), in which dozens of different proteins can be detected on single cells simultaneously using antibodies differentially labeled with heavy metals and analyzed by mass cytometry. The investigators applied a “bar code” strategy to separately label leukocytes from tumor, normal tissue, and blood from a single patient using three differently labeled anti-CD45 antibodies. Additional data were obtained by multiplexed immunohistochemical staining of tumor tissue, assays of cytokines secreted by cultured cells, and single-cell RNA sequencing.

Among the key findings were a reduced cytotoxic T cell/regulatory T cell ratio in tumor as compared with normal lung tissue and a marked reduction and functional impairment of natural killer cells in the tumors. The authors also documented decreased numbers of CD141+ dendritic cells (DCs) and an increase in monocyte-derived CD1c+ DCs in the tumors compared with normal lung, which could potentially result in impaired tumor-specific T cell priming. The tumor macrophages were also distinct from those in normal lung, expressing more peroxisome proliferator–activated receptor γ and interleukin-6 and less CD86, which is consistent with an immunosuppressive, protumorigenic phenotype. This study is one of several recently reported studies demonstrating the power of multiparameter single-cell analyses in defining the immune landscape in tumors. What makes the study by Lavin et al. particularly noteworthy is the focus on innate immune responses in early tumors, which may be targeted to enhance T cell responses.

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