Making and circumventing tolerance to cancer

Abstract

The interactions between cancer and immune cells are complex. Even though the mutations that cause cancer can create new antigens that are potentially ''visible'' to T cells, in most experimental model systems the growth of tumors is accompanied by induction of T-cell tolerance towards the tumor. How tolerance to tumors is induced and how tolerance can be broken by immunotherapy have been a main focus in cancer immunology. Here, we discuss experimental models used in cancer immunology. We argue that, while it is obviously easy for tumors to induce tolerance, it should be as easy to circumvent tolerance by the adoptive transfer of tumor-antigen-reactive T cells. Effective adoptive T-cell therapy has become feasible by methods to identify TCR against tumor-associated (self-) antigens with high affinity and to graft a new antigen specificity to patients' T cells by TCR gene transfer.Key words: Adoptive T-cell therapy . Experimental cancer models . Tolerance .Tumor immunity IntroductionThe choice of experimental systems that adequately reflect cancer development in humans is essential to better understand the complex interactions between tumors and the immune system. Historically, transplantable tumor models or tumors induced by oncogenic viruses were investigated [1]. Additionally, chemical carcinogenesis and skin tumor induction by UV-light were used to analyze immune responses to tumors [2,3]. Cancer-prone mice expressing an oncogene in a tissue-specific fashion have been used to employ immunotherapeutic strategies [4]. The Cre-LoxP recombination system and drug-inducible oncogene induction represent more recent technologies allowing spatio-temporal tumor induction that better mimic cancer development in humans [5]. Additionally, gene-deficient mice with various immune deficiencies and mice with transgenic T-cell receptors specific for tumor antigens were used to analyze the role of the immune system for tumor development. Data from all these experimental cancer models have contributed to our current understanding of tumor-immune system interactions. Importantly, recent developments have demonstrated the power of adoptively transferred T cells to reject large tumors. Here, we give a short overview of experimental cancer models, the discoveries they have brought about and the limitations they have. Finally, we argue that adoptive T-cell therapy (ATT) not only holds the greatest promise to break (or more precisely to circumvent) tolerance against established tumors but also that it is a feasible approach in the clinic, if combined with genetic engineering of antigen-specific T cells. Experimental cancer modelsTransplantable tumor modelsThe observation that tumors can be transplanted from one animal to another dates back more than a century [6]. Initial studies were difficult, because mice were not inbred and transplantation On the other hand, many important discoveries have been made in tumor transplantation models. For example, the necessity of tumors to induce angiogenesis [12], the role of the tumor stroma for t...

Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies

“…The transfused redirected or bi-functional T cell numbers should increase rapidly in the patient through homeostatic expansion via IL-7 and IL-15 [23], although this expansion may be compromised by high tumour burdens [37]. The cytotoxic conditioning regimen has a dual function, in that it may also kill a proportion of the tumour cells, releasing antigen and enhancing tumour recognition [59]. There is also evidence that irradiation enhances adhesion molecule expression, facilitating movement of the TAAtargeted T cells into tumour sites [59,60].…”

“…The cytotoxic conditioning regimen has a dual function, in that it may also kill a proportion of the tumour cells, releasing antigen and enhancing tumour recognition [59]. There is also evidence that irradiation enhances adhesion molecule expression, facilitating movement of the TAAtargeted T cells into tumour sites [59,60]. However, the conditioning regimen may also pose a risk of morbidity or mortality to the patient, so selective depletion of lymphocytes post-transfer may offer a safer option [23].…”

“…Persistence may be enhanced by introducing TAA-specific TCR-ab genes into haematopoietic stem cells, which would result in continuous production of the enhanced T cells through homeostasis [59]. Although there has been some success with this method, it is unclear whether the transduced cells would persist following thymic education [59].…”

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

“…Recent cancer-immunotherapy strategies attempt to overcome the immunotolerance associated with cancer [8,9]. Anti-CD25 Ab have been used to deplete CD25 1 nTreg populations, since they have been shown to suppress antitumor immunity [10,11].…”

Molecular Pathways: Comparing the Effects of Drugs and T Cells to Effectively Target Oncogenes

“…Optimal affinity means that the T cells are restricted to human self-MHC molecules and recognize the peptide antigen as foreign, for example, as representatives of the nontolerant repertoire. By using peptide/MHC multimers, specific T cells of the transgenic mice can be sorted, then, human TCRs isolated, for example, by single cell PCR, the TCRs optimized for efficient expression while avoiding mispairing with endogenous TCR and are used for transduction of patients' T cells with viral vectors (54,55). We anticipate that such engineered T cells, comparable with the Tet-TagLuc tumor model, will exert optimal effector function within the tumor microenvironment and not only eliminate the cancer cells but also destroy the tumor vasculature by release of large amounts of IFN-g and TNF-a, thereby indirectly eliminating potential escape variants.…”