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The immune system developed to respond against foreign materials, including pathogenic microorganisms, invading the body and has a basic characteristic—not attacking self-cells (immunological tolerance). Although the immunosurveillance theory was proposed in the 1960s, in which immune cells always eliminate potentially tumorigenic self-derived altered cells, there has been much debate on the presence of immunosurveillance, on cancer cell recognition as non-self and on immunological eradication (immunotherapy) of cancer cells that are found in clinics and have already evaded immune defenses. However, recent research using various murine tumor models demonstrated the presence of immunosurveillance by T cells, NK cells and other innate immune cells, as well as immune-editing (the loss from the cancer cells of highly immunogenic T-cell antigens and the acquisition of immune-resistance and immunosuppressive activities) and consequent immune-evasion during long-term cancer development processes, which is also likely to occur in humans.
Durable clinical effects following immune-checkpoint blockade and T-cell-based adoptive cell therapy in cancer patients who had failed standard chemotherapy indicate the presence of anti-tumor immune responses even in patients with advanced cancer and suggest that immunotherapy is certainly possible at least for some of the cancer patients. However, these studies also demonstrated individual differences in immune status that may be related to responses to various cancer therapies (not only immunotherapy but also other standard cancer therapies including surgery, chemotherapy and radiation therapy).
The immune status in cancer appears to be defined by cancer cell characteristics (e.g. passenger and driver mutations and oncogene activation), host immune reactivity (e.g. polymorphisms of immunity-related molecules) and environmental factors (e.g. smoking, intestinal microbiota, obesity and infection history). Therefore, further understanding of human cancer immunopathology, particularly mechanisms of individual differences of immune status, is important to improve current cancer immunotherapies, possibly through the identification of biomarkers for personalized therapy and therapeutic targets for combinatorial immunotherapy.
This is the second part (“Immunopathology”) of our Special Issue “Cancer Immunology”; it comprises five review articles discussing recent progress in this area, particularly the understanding of immunopathology in tumor microenvironments of human cancers and future directions of research including combinations of multi-omics studies and immunological analyses. Franck Pagès et al. discuss the roles of T-cell infiltration in tumors (the “Immunoscore”) in post-surgery prognosis and the development of new diagnostics for better patient management beyond the standard cancer spread-based TNM classification (1). Stefani Spranger discusses the mechanisms of T-cell suppression in local tumor sites in T-cell-inflamed cancer (adaptive resistance) and of immunosuppression in T–cell-noninflamed cancers and their potential modulation (2). Tomonori Yaguchi and Yutaka Kawakami discuss the mechanisms of suppression of anti-tumor T cell responses initiated by gene alterations in cancer cells (e.g. oncogenes) and their potential modulation for development of novel personalized combinatorial immunotherapy (3). Yoshiko Takeuchi and Hiroyoshi Nishikawa discuss the roles of immunosuppressive regulatory T cells in human cancer and their modulating strategies (4). Timothy Chan et al. discuss important roles of DNA mutation-derived tumor antigens (neoantigens), which may be the major targets for tumor-eliminating T cells induced after immune-checkpoint blockade (5).
I would like to thank all of the authors for these excellent and thought-provoking articles. The immunotherapy of cancers was covered in the first part of the Special Issue.