Complex problems do not necessarily require complex solutions (80,53)
. Indentifying the common, downstream, mechanisms that lead to the immune-mediated tissue destruction in different conditions may allow the development of novel target treatments without requiring the understanding of the individual phenomenologies.
In 1969, in a seminal manuscript entitled ‘Immunological paradoxes: theoretical consideration in the rejection or retention of graft, tumors and normal tissue’, Jonas Salk proposed that chronic infections, allograft rejections, autoimmune disorders and cancers belong to a common phenomenon that he named the “delayed allergy reaction” (81)
. This outstanding observation stated almost half a century ago, seems to have found today its molecular explanation.
Although mechanism triggering tissue-specific destruction (TSD) differ among distinct immune pathologies, we proposed that TSD follows a common pathway which we termed the “immunologic constant of rejection (ICR)”(53)
. We formulated four axioms that summarize the phenomenon: 1) TSD does not necessarily occur because of non-self recognition but also occurs against self or quasi-self; 2) the requirements for the induction of a cognate immune response differ from those necessary for the activation of an effector one; 3) although the prompts leading to TSD vary in distinct pathologic states, the effector immune response converges into a single mechanism; and 4) adaptive immunity participates as a tissue-specific trigger, but it is not always sufficient or necessary (53)
The limited work performed by our group so far studying in real-time the events occurring before and during therapy in the tumor microenvironment suggests that immune rejection is associated with the activation of ISGs accompanied by the activation of genes that are expressed naturally by NK cells and by CD8 T cells upon activation. Among them we observed that NK and CD8+ T cells effector function genes (e.g. perforin, granzymes and granulysin) seem to predominate during the switch to acute rejection. Interestingly, accordingly with other human studies investigating different processes, the activation of such ‘NK like’ mechanism appears to be a convergent molecular mechanism of several forms of immune-mediated process. We recently summarized the common functional units that, when TSD destruction occurs, are activated in a coordinate fashion:
- the STAT-1/IRF-1/T-bet/IFN-γ, IL-15 path
- the Granzyme A/B, TIA-1 pathway
- the CXCR3 ligand chemokine pathway
- The CCR5 ligand chemokine pathway
We observed, in different disease models, their presence; studies in humans have identified these signatures to be associated with improved survival of patients with colon, lung and ovarian cancer or melanoma (82,83,84,85,86,87,73)
; the same patterns were observed in neoplastic lesions responsive to immunotherapy both in humans (42,41,43,37)
and in experimental models (88)
. In transpantology, several studies have reported the activation of the same pathway during the occurrence of acute allograft rejection (50,89,90,52,51,91)
. In particular Saint-Mezard et al. (51)
, by comparing three independent microarray data sets of kidney biopsies, identified IRF-1 as the main transcription factors that regulated the 70 genes consistently represented during acute allograft rejection episode. Imanguli et al (92)
, observed similar patterns by studying biopsies of tissues suffering chronic graft versus host disease and similar patters where observed in the liver during clearance of HCV infection (93,94,95,96,97)
. Recently similar signatures were observed in the destructive phases of acute cardiovascular events (98,99)
, chronic obstructive pulmonary disease (100)
and placental villitis (101)
We believe that decrypting the codes that govern the balance between tolerance and rejection, as well as the events that can suddenly induce the switch from an indolent process to a destructive one, may allow to identify a key molecular process, the targeting of which could represent the rational for the development of a new-generation cancer therapy.
Tools are available nowadays to study biological processes in their globality. The study of individual genetic predisposition to disease and response to treatment could be combined with that of epigenetic changes during life and disease progression and that of real-time adaptation of the transcriptional profile of biological samples in relevant conditions. The problem resides in the availability of relevant samples to study. In particular, functional genomics studies rely on the measurement of messenger RNA levels that are very susceptible to metabolism and degradation. Thus, only carefully and prospectively collected samples are usually worth studying. The understanding of the biology of cancer cells, their relationship with the host and their response/adaptation to therapy would be an achievable goal if clinical studies were designed to answer these questions and not only to test the potency of a given treatment (21)
. With the purpose of co-coordinating future clinical efforts in this line several issues will need to be considered beyond genetic profiling to acquire a more global sophistication in the design and conduct of clinical trials in the future (37)