This book represents an up-dated summary of the state of the art of the characterization of cancer stem cell/ cancer initiating cell (CSC/CIC) properties. An overview of the definition and biological properties of CSCs/CICs as well as the role of these cells in determining the resistance to standard and immune-based therapies is provided. It also discusses limitations in the achievement of a definitive biological characterization of CSCs/CICs due to their high extent of plasticity and heterogeneity that is also mutually driven by the interaction of these cells with the tumor microenvironment. The limitations in targeting CSCs/CICs with immunotherapy are also explained together with explorative combination approaches that could increase the susceptibility of these cells to the recognition by immune cells. This book is conceived for a broad audience, including students, teachers, scientific experts. The critical revision of available results in terms of immunological profile of CSCs/CICs and the efficacy in targeting these cells by immunological approaches, results in a comprehensive and up to date recapitulation of the field and provides interesting suggestions on how to focus future investigations in order to assess the role of CSCs/CICs as prognostic and predictive biomarkers of responsiveness to therapies for cancer patients.

In recent years much progress has been made in knowledge and understanding of the biology of cutaneous melanoma. In this respect etiological factors, prognostic factors, antigen expression of melanoma cells, immune response and mechanisms of metastasis formation have to be mentioned. It is the purpose of this book to give a review on fundamental aspects, diagnosis and prognosis, and treatment of cutaneous melanoma and precursor lesions. Moreover, previously unpublished new data are presented. A post-graduate Boerhaave course "Cutaneous Melanoma and Precursor Lesions" was held at Leiden University on 12 and 13 April, . 1984. The proceedings are contained in this volume. The editors would like to thank all speakers and chairpersons on the course, the Boerhaave Committee for its contribution to the organisation of the course, Upjohn Nederland for its financial support and Mrs. I.A. Kruyff for her secretarial assistance. Dirk Ruiter, Kees Welvaart and Soldano Ferrone, Leiden and Valhalla (NY), June, 1984. VII CONTENTS Preface v Contents VII List of First Authors with Co-Authors XI PART I: FUNDAMENTAL ASPECTS. The epidemiology of melanoma R.M. MACKIE The molecular biology of carcinogenesis 9 A.W.M. VAN DER KAMP AND N.G.J. JASPERS 19 Human melanoma associated antigens identified with monoclonal antibodies: characterization and potential clinical application P.G. NATALI, R. CAVLIERE, M. MATSUI, G. BURAGGI, L. CALLEGARO, and S. FERRONE Cellular and molecular parameters of tumor progression in 38 human malignant melanoma J. BRUEGGEN, E.B. BROECKER, L. SUTER, K. REDMANN, and C.

The ever-expanding research on human cancer has resulted in numerous technical and conceptual advances during the last few years. Serological, structural, and biological char acterization of human melanoma constitutes one area of research that has received consid erable attention from researchers and clinicians and has generated new and exciting infor mation. In this volume, we have attempted to assemble work on topics that produced some of the most recent advances. We asked each author to describe and interpret his most cur rent research and, whenever possible, to compare and contrast it with work of other inves tigators in the field. We have been careful not to impose our viewpoints except in contri butions from our own laboratories, since we want to provide the reader with as many divergent and sometimes opposing viewpoints as feasible. Therefore, we have not been overly concerned with overlaps in some individual topics. We hope that this volume will provide the reader with a well-balanced overview of current problems and ideas in a par ticular area of cancer research. We wish to express our thanks to all contributors for their timely and very interesting manuscripts, and we sincerely hope that the reader will enjoy this volume and benefit as much from it as we did. R. A. Reisfeld S. Ferrone La Jolla ix Contents CHAPTER 1 Immunogenetics of Melanoma RONALD T. ACTON, CHARLES M. BALCH, BRUCE BUDOWLE, RODNEY C. P. Go, JEFFREY M. ROSEMAN, SENG-jAW SOONG, AND BRUCE O. BARGER 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Malignant melanoma is the focus of investigations which range from basic re search to clinical trials with conventional therapy and with biological response modifiers. The involvement of investigators with different backgrounds in combi nation with recent progress in biotechnology has facilitated the characterization of the antigenic profile of melanoma cells, the analysis of the structural and function al properties of melanoma-associated antigens, and the application of immuno diagnostic and immunotherapeutic approaches to melanoma. As a result, a large body of information about various aspects of melanoma has been rapidly accumu lated during the past few years. In organizing this book I aimed at providing a readily available source of infor mation on the current research in melanoma. To this end I invited investigators with active research programs to contribute chapters describing and discussing the significance of their most recent results. To facilitate the preparation of the manu scripts and to avoid duplicating other recently published books on melanoma, I discouraged the contributors from providing extensive reviews of the literature on the various topics. Although I made every effort to be as complete as possible in the selection of the contributors, while writing this preface I realized that I had overlooked at least three investigators whose work should have been included.

This volume deals with the structure and function of molecules that have, during the last decade, turned out to have a central role in immune responses. Trans plantation antigens were discovered and characterized by Gorer about 50 years ago, and the biological basis for the unequalled complexity of their variability between individuals within a species, in spite of extreme conservation between species, was the subject of intense research and discussion for many years. During the days of belief in "immune surveillance" against spontaneously developing tumors, it was suggested that histoincompatibility between members of one species would prevent cancer from being a contagious disease and thus a threat to the species. Immunologists involved in human transplantation had to learn and care about the complexity, especially after 1967, when it was found that HLA antigens were the products of the human MHC. Rejection of HLA-identical sib kidney grafts was so rare, even in those days, that cases of rejection were described in scientific papers."

In recent years much progress has been made in knowledge and understanding of the biology of cutaneous melanoma. In this respect etiological factors, prognostic factors, antigen expression of melanoma cells, immune response and mechanisms of metastasis formation have to be mentioned. It is the purpose of this book to give a review on fundamental aspects, diagnosis and prognosis, and treatment of cutaneous melanoma and precursor lesions. Moreover, previously unpublished new data are presented. A post-graduate Boerhaave course "Cutaneous Melanoma and Precursor Lesions" was held at Leiden University on 12 and 13 April, . 1984. The proceedings are contained in this volume. The editors would like to thank all speakers and chairpersons on the course, the Boerhaave Committee for its contribution to the organisation of the course, Upjohn Nederland for its financial support and Mrs. I.A. Kruyff for her secretarial assistance. Dirk Ruiter, Kees Welvaart and Soldano Ferrone, Leiden and Valhalla (NY), June, 1984. VII CONTENTS Preface v Contents VII List of First Authors with Co-Authors XI PART I: FUNDAMENTAL ASPECTS. The epidemiology of melanoma R.M. MACKIE The molecular biology of carcinogenesis 9 A.W.M. VAN DER KAMP AND N.G.J. JASPERS 19 Human melanoma associated antigens identified with monoclonal antibodies: characterization and potential clinical application P.G. NATALI, R. CAVLIERE, M. MATSUI, G. BURAGGI, L. CALLEGARO, and S. FERRONE Cellular and molecular parameters of tumor progression in 38 human malignant melanoma J. BRUEGGEN, E.B. BROECKER, L. SUTER, K. REDMANN, and C.

This book represents an up-dated summary of the state of the art of the characterization of cancer stem cell/ cancer initiating cell (CSC/CIC) properties. An overview of the definition and biological properties of CSCs/CICs as well as the role of these cells in determining the resistance to standard and immune-based therapies is provided. It also discusses limitations in the achievement of a definitive biological characterization of CSCs/CICs due to their high extent of plasticity and heterogeneity that is also mutually driven by the interaction of these cells with the tumor microenvironment. The limitations in targeting CSCs/CICs with immunotherapy are also explained together with explorative combination approaches that could increase the susceptibility of these cells to the recognition by immune cells. This book is conceived for a broad audience, including students, teachers, scientific experts. The critical revision of available results in terms of immunological profile of CSCs/CICs and the efficacy in targeting these cells by immunological approaches, results in a comprehensive and up to date recapitulation of the field and provides interesting suggestions on how to focus future investigations in order to assess the role of CSCs/CICs as prognostic and predictive biomarkers of responsiveness to therapies for cancer patients.

With this book we* want to address young graduate students, clini cians involved in transplantation, and technicians in transplantation immunology laboratories. The volume should give a comprehensive but basic, up to date introduction to the structure, function, and clinical importance of the HLA system. We believe that there is a need for such a survey, and think that the present level of our knowledge is an optimal occasion for publication. A significant number of ques tions have now been resolved, and our knowledge has reached a level of sophistication that provides the basis for additional questions and answers. Although the emphasis of this book is on the role of HLA anti gens in clinical transplantation, their involvement in other clinical contexts is also discussed. The main focus is on the human MHC an tigenic system, but MHC systems in other species are described as they contribute to our understanding of the structural and functional characteristics of HLA antigens. Some important issues related to laboratory techniques are also covered. The contributors have a close affiliation to the field of transplan tation immunology. A majority have even been playing important roles in unraveling the HLA system and its functions. We believe this has contributed significantly to the quality and clinical and practical relevance of the book. As editors, we drew up the principal guidelines and took care that the chapters can be read as separate entities, although this invariably results in some overlapping.