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In this issue of Immunity, apply an inductive approach to pathway discovery identifying modular units that govern human immune biology. [Copyright &y& Elsevier]

Numerous analyses of large patient cohorts identified specific patterns of immune activation associated with patient survival. We established these as the immune contexture, encompassing the type, functional orientation, density, and location of adaptive immune cells within distinct tumor regions. Based on the immune contexture, a standardized, powerful immune stratification system, the Immunoscore, was delineated. The immune contexture is characterized by immune signatures also observed in association with the broader phenomenon of immune-mediated, tissue-specific destruction. We defined these as the immunologic constant of rejection. Predictive, prognostic, and mechanistic immune signatures overlap, and a continuum of intratumor immune reactions exists. The balance between tumor cell growth and elimination may be tipped upon a crescendo induced by immune manipulations aimed at enhancing naturally occurring immunosurveillance. Here, we propose a broader immunological interpretation of these three concepts—immune contexture, Immunoscore, and immunologic constant of rejection—that segregates oncogenic processes independently of their tissue origin. [Copyright &y& Elsevier]

Summary: Tumor progression is accompanied by an altered myelopoiesis causing the accumulation of immunosuppressive cells. Here, we showed that miR-142-3p downregulation promoted macrophage differentiation and determined the acquisition of their immunosuppressive function in tumor. Tumor-released cytokines signaling through gp130, the common subunit of the interleukin-6 cytokine receptor family, induced the LAP∗ isoform of C/EBPβ transcription factor, promoting macrophage generation. miR-142-3p downregulated gp130 by canonical binding to its messenger RNA (mRNA) 3' UTR and repressed C/EBPβ LAP∗ by noncanonical binding to its 5' mRNA coding sequence. Enforced miR expression impaired macrophage differentiation both in vitro and in vivo. Mice constitutively expressing miR-142-3p in the bone marrow showed a marked increase in survival following immunotherapy with tumor-specific T lymphocytes. By modulating a specific miR in bone marrow precursors, we thus demonstrated the feasibility of altering tumor-induced macrophage differentiation as a potent tool to improve the efficacy of cancer immunotherapy. [Copyright &y& Elsevier]

Summary We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics. Graphical Abstract Highlights • Different escape mechanisms delineated by lack of adaptive immunity or immunoediting • Non-recurrent clones are immunoedited; progressing clones are immune privileged • Immunoediting and Immunoscore are predictive factors of metastasis recurrence • Parallel selection model describes clonal immunoediting and tumor evolution A longitudinal analysis of clonal evolution of tumors across multiple tissues identifies a parallel selection model that explains the role of immune editing in controlling metastatic growth. [ABSTRACT FROM AUTHOR]