Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis

The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) environment closely interact by cell-to-cell contact and/or via soluble factors, also generating a tumor-permissive soil. These dangerous liaisons have been investigated for pillars of tumor immunology, such as tumor associated macrophages and T cell subsets. Here, we reviewed and discussed the contribution of selected innate immunity effector cells, namely neutrophils and natural killer cells, as \u201csoloists\u201d or by their \u201cdangerous liaisons\u201d, in favoring tumor progression by dissecting the cellular and molecular mechanisms involved

The Molecular and Cellular Basis of Tumor Rejection After Vaccination With Mammary Adenocarcinoma Cells Transduced With the MHC Class II Transactivator CIITA

CD8+ T cell responses are major players of tumor eradication in various vaccination protocols. However, an optimal stimulation of CD4+ T helper cells is required for both priming and maintenance of the effector CTL response against the tumor. In this study we show that the murine mammary adenocarcinoma cell line TS/A, a highly malignant MHC-II-negative tumor, is rejected in vivo if genetically engineered to express MHC-II molecules by transfer of the MHC-II transactivator CIITA. TS/ACIITA cells are fully rejected by 93% of the syngeneic recipients and have a significantly lower growth rate in the remaining 7% of animals. Rejection requires CD4+ and CD8+ cells. CD4+ T cells are fundamental in the priming phase, whereas CTLs are the major anti-tumor effectors. All tumor rejecting animals are protected against rechallenge with the parental TS/A tumor. Immunohistochemical data at day 5 post-inoculation showed an higher infiltrate of CD4+ T cells in mice bearing TS/A-CIITA, than in mice bearing the TS/A tumor. Subsequently, from day 7 trough day 10, TS/A-CIITA tumors showed higher number of both CD4+ and CD8+ cells, dendritic cells, together with massive necrosis. The frequency of IFN-αsecreting splenocytes early after inoculations was also assessed by an ex vivo ELISPOT assay. Only the rejecting TS/A-CIITA animals showed an high frequency of IFN-αsecreting cells (between 80 and 120/106 splenocytes). Importantly, CD4 and CD8 depletion experiments revealed that at the time of tumor resolution the major cell population recognizing the TS/A-CIITA cells was of CD4 origin. This is the first example of successful tumor vaccination by genetic transfer of CIITA. These results open the way to a possible use of CIITA for increasing both the inducing and the effector phase of the anti-tumor response. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 200

The complex liaison between cachexia and tumor burden

Abstract. The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcino-genesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initia\uaction, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifi\uaccally, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at \u2018hijacking\u2019 the crypt stem cell niche from a status characterized by the main\uactenance of homeostasis to local chronic inflammation, with the prospect of initiating neoplastic transformation in that site

New strategies of mammary cancer vaccination

A new strategy of vaccination against mammary tumors, extendible to tumors of distinct histological origin, based on the administration of tumor cells genetically modified to express major histocompatibility complex (MHC) class II gene products, will be described. Expression of MHC class II molecules in solid tumors, generally lacking these molecules, is achieved by transfecting tumor cells with the MHC class II transactivator (CIITA), the major regulator of the entire family of MHC class II genes. CIITA is encoded by the AIR-1 locus, discovered in our laboratory. The rationale underlying this approach consists in making the tumor cells a sort of surrogate antigen presenting cells for MHC-II-restricted CD4 + T helper (TH) cells. Indeed, it is known that an efficient adaptive immune response against cancer cells can only be achieved if tumor-specific TH cells, the key lymphocyte subpopulation required to trigger both humoral and cellular effector mechanisms, are optimally stimulated. Results from our group show that: (a) CIITA-modified tumor cells can be rejected in vivo by syngeneic immunocompetent mice; (b) this rejection is mediated primarily by CD4 + TH lymphocytes that activate cytolytic CD8 + T cell effectors; (c) tumor-rejecting mice are resistant to challenge with parental unmodified tumor cells and display long term immune memory; (d) anti-tumor vaccination can be reproduced by using inactivated, nonreplicating CIITA-transfected tumor cells; (e) immune effectors and particularly primed CD4 + TH cells can be used successfully in approaches of immunotherapy of established tumors. These results open the way to envisage a possible use of CIITA-modified mammary tumor cells as a vaccine for increasing both the inducing and the effector phase of the anti-tumor immune response in human settings