Abstract The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Together with Galon's (1,2) and other groups, we propose an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells (3). As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process(4). Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Indeed, these signatures that define a good prognostic cancer phenotype are similar to those associated with the broader phenomenon of immune-mediated, tissue-specific destruction (TSD) in other immune pathologies such as regression of cancer during immunotherapy, allograft rejection, graft versus host disease, flares of autoimmunity or destruction of virally infected cells to clear intra-cellular pathogens during acute infection. Direct human observations collected by studying tissues during the acute phases of TSD demonstrated a convergence toward a common final mechanism including the activation of interferon stimulated genes, genes associated with immune effector function and the presence of a restricted group of chemokines targeting activated T and natural killer cells. We defined this set of genes “the immunologic constant of rejection” (ICR)(5,4). In cancer, it appears that the ICR genes are present not only during the acute phase of rejection, but also are expressed though with lower intensity in tumors that bear better prognosis and in tumors most likely to response to immune therapy. In particular, we recently followed a limited set of melanoma metastases undergoing immunotherapy with systemic high-dose interleukin-2. As previously observed (6), metastases that underwent complete regression following therapy differed in their transcriptional profile from non responding ones even before treatment (7) and expressed a subset of ICR genes. By serially biopsying the same metastases using minimally invasive techniques, we observed that during treatment, the responsive metastases underwent a further activation of ICR genes that was both qualitative and quantitative while the non-responding ones remained silent. This observation suggests that immune rejection of cancer is part of the intrinsic biology of individual cancers which may be predisposed to immune responsiveness and their natural history can be modulated with interventions that can enhance a naturally occurring phenomenon. It remains, however, unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Recent work from our group suggests that a combination of the two could be responsible for this multifactorial event. Analysis of two cases in which patients with melanoma experienced a mixed response during therapy suggests that the activation of ICR genes and consequently immune rejection of cancer is genetically determined by the tumor phenotypes as distinct tumors responded differently in the same patient at the same time, therefore, eliminating the genetic background of the host and/or environmental factors as determinants in these cases (8). On the other hand, recent work also from our group identified a polymorphism of the interferon-regulatory factor-5 (IRF-5) as a potential predictor of non-responsiveness to immunotherapy (9). Thus, we propose a hierarchical model of immune responsiveness in which the likelihood of a tumor to respond to immunotherapy is first dependent upon a check-point determined by the genetic background of the patient. As a second check point, in patients genetically predisposed to respond to therapy, is the genetic makeup of individual cancers that can further determine their responsiveness. Finally, as a third check point, environmental factors such as quality, intensity and type of therapy may modulate, within each cancer the likelihood of response. As several of these determinants are observed in other forms of TSD such for instance systemic lupus erythematosus, we propose, that cancer rejection in response to immunotherapy, it an aspect of auto-immunity that targets cancer-specific biological processes and it occurs only when a full-fledged acute inflammatory status is reached with complete activation of ICR genes.
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Apr 1, 2019
David A Ostrov + 2
Open Access
