Volume 39, Issue 1, Pages 11-26 (July 2013) The Continuum of Cancer Immunosurveillance: Prognostic, Predictive, and Mechanistic Signatures  Jérôme Galon, Helen K. Angell, Davide Bedognetti, Francesco M. Marincola  Immunity  Volume 39, Issue 1, Pages 11-26 (July 2013) DOI: 10.1016/j.immuni.2013.07.008 Copyright © 2013 Elsevier Inc. Terms and Conditions

Immunity 2013 39, 11-26DOI: (10.1016/j.immuni.2013.07.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 1 Graphical Representation of the Immune Contexture, the Immunoscore, and the ICR The immune contexture is defined as the type, functional orientation, density, and location of adaptive immune cells within distinct tumor regions. The parameters establishing the immune contexture are comprised of the density of CD3+, CD8+, and CD45RO+ T cells and their location at the tumor center and invasive margin combined with the quality of tertiary LIs. Numerous analyses of large patient cohorts confirmed an association between these patterns and favorable disease outcome. The Immunoscore is derived from three aspects of the immune contexture: the type, density, and location of immune cells. The functional orientation of the immune contexture is characterized by immune signatures qualitatively similar to those predicting response to immunotherapy, which are observable in association with the broader phenomenon of immune-mediated, tissue-specific destruction. These signatures are detectable during regression of cancer following immunotherapy, allograft rejection, GVHD, flares of autoimmunity, or destruction of virally infected cells to clear intracellular pathogens. We defined them as the immunologic constant of rejection (ICR). Genes underlying Th1 polarization, related chemokines (CXCR3 and CCR5 ligands), and genes associated with the activation of cytotoxic mechanisms more frequently described in association with the broader phenomenon of immune-mediated, tissue-specific destruction (ICR genes) are in bold. Immunity 2013 39, 11-26DOI: (10.1016/j.immuni.2013.07.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 2 Overlap between the Immune Contexture, the Immunoscore, and the ICR The top panel is a diagrammatic representation of the immune contexture defined in cancer and its overlap with the Immunoscore and with the ICR seen in other diseases. The bottom panel highlights the characteristics of these three concepts. The immune contexture represents the complexity of the immune parameters within the tumor microenvironment associated with patient survival; the Immunoscore represents a standardized, simple, and powerful immune stratification system, proposed as a novel method for routine testing; and the ICR represents the immune gene signatures observed in association with tissue-specific destruction. Immunity 2013 39, 11-26DOI: (10.1016/j.immuni.2013.07.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 3 The Molecular Continuum between Prognostic, Predictive, and Mechanistic Signatures (A) Postulated impact of cancer treatments on the tumor microenvironment. Therapies designed to target tumor cells can also induce changes in the immune response and tumor microenvironment. These responses are amplified in the setting of immunotherapies, which boost naturally occurring (but suppressed) antitumor immune response. In some patients this intratumoral immune response can slow down tumor growth or eventually mediate long-lasting tumor regression. Chemo, chemotherapy; Radio, radiotherapy; Small molec, small molecules (kinase inhibitors); Tumor-mAbs, tumor-directed antibodies; Immune-mAbs, immune-directed antibodies (checkpoint blockade inhibitors); TLR, toll-like receptor agonists; CYT, cytokines (i.e., IL-2); VAC, vaccines; ACT, adoptive cell-transfer therapy. (B) Proposed quantitative continuum between prognostic, predictive and mechanistic signatures. It could be hypothesized that the lowest level of immune activation is a feature of predictive signatures that cannot affect tumor growth (or risk of recurrence when the primary tumor is excised) in natural conditions. It is followed by prognostic signatures of insufficient intensity to cause cancer eradication but capable of controlling tumor growth (or tumor recurrence). The maximal intensity of immune response (captured by mechanistic signatures) occurs in lesions that are about to regress after immunotherapy administration. (C) Potential qualitative difference in overlap between immune and nonimmune prognostic, predictive, and mechanistic signatures. Only immune signatures measure the status of activation of a naturally protective mechanism, which, if successfully elicited, can lead to tumor regression. For this reason it is probable that predictive immune signatures will overlap (qualitatively) with the prognostic and the mechanistic ones. This is not the case, however, of nonimmune-related signatures, which, in general, measure cancer cell centric characteristics. Immunity 2013 39, 11-26DOI: (10.1016/j.immuni.2013.07.008) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 4 Possible Mechanisms Contributing to the Overlapping Signatures of the Immune Contexture and the ICR A schematic describing the potential cancer-centric and host-centric contributing factors, leading to the immune contexture and ICR. These are counter balanced by immune escape mechanisms. PAMPS, pathogen-associated molecular pattern. Immunity 2013 39, 11-26DOI: (10.1016/j.immuni.2013.07.008) Copyright © 2013 Elsevier Inc. Terms and Conditions