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CONTEMPORARY TOPICS
IN IMMUNOBIOLOGY
VOLUME 10
CONTEMPORARY TOPICS IN IMMUNOBIOLOGY
General Editor: M. G. Hanna, Jr.
Frederick Cancer Research Center Frederiek, Maryland
Editorial Board: Max O. Cooper
Unil'eYsity of Ala ham a Birmini!,ham, Alabama
John J. Marchalonis University of South Carolina Charleston, South Carolina
G. J. V. Nossal The Walter & Eliza Hall institute ojMedical Research
Victoria, Australia
Victor Nussenzweig New York University School of Medicine
New York, New York
George W. Santos .fohns Hopkins Unil'l'rsitl'
Baltimore. Maryland
Ralph Snyderman Duke Unil'eYsitl' Medical Center
Durham, North Carolina
Osias Stutman Sloan·Kettcrini!, ilzstitute for Callcer Research
/Vew York. New York
Noel L. Warner Unit'crsit)' of New Mexico Alhuquerque. New Mexico
William O. Weigle Scripps Clinic alld Research FOlllldatiOiz
I.a .folia. California
A Continuation Order Plan is availahlc for this series. A continuation order will bring deiivery uf eadl lIew VlJlumc immediately upon puh!il..'ation. Volumes 3re hil!ed t'nly UP!.Hl actual shipment. For further information please Contact the publisher.
CONTEMPORARY TOPICS
IN IMMUNOBIOLOGY
VOLUME 10 In Situ Expression of Tumor Immunity
EDITED BY
ISAAC P. WITZ Department of Microbiology
The George S. Wise Faculty of Life Sciences Tel Aviv University
Tel Aviv, Israel
and
M. G. HANNA, JR. Frederick Cancer Research Center
Frederick, Maryland
Springer Science + Business Media, LLC
The Library of Congress cataloged the first volume in this series as follows:
Contemporary topics in immunobiology. v. 1-1972-New York, Plenum Press.
v. illus. 24cm. annual.
1. Immunology-Periodicals. QR180.C632 ISSN 0093-4054 Library of Congress
574.2'9'05 rev 72 [r74c2]
79-179761 MARC-S
ISBN 978-1-4684-3679-2 ISBN 978-1-4684-3677-8 (eBook) DOI 10.1007/978-1-4684-3677-8
© 1980 Springer Science+Business Media New York Originally published by Plenum Press, New York in 1980
Softcover reprint of the hardcover 1st edition 1980
All righ ts reserved
No part of this book may be reproduced, stored in a retrieval system, or transmiHed, in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Contributors
Ora Amitai
Gideon Berke
C. D. Bucana
Robert Evans
M. Fopp
P. Frost
U. Ga1ili
James Gerson
G. Yancey Gillespie
M. G. Hanna, Jr.
Department of Microbiology The George S. Wise Faculty of Life Sciences Tel A viv University Tel A viv, Israel Deparment of Cell Biology The Weizmann Institute of Science Rehovot, Israel Cancer Biology Program NCI Frederick Cancer Research Center Frederick, Maryland 21701 The Jackson Laboratory Bar Harbor, Maine 04609 Department of Tumor Biology Karolinska Institute Radiumhemmet, Karolinska Sjukhuset S-I04 01 Stockholm 60, Sweden Present address: Department of Oncology and Hematology Clinic of Medicine Kanton Spital CH-9007 St. Gallen, Switzerland Department of Immunology and Microbiology Wayne State University Detroit, Michigan 48201 Department of Tumor Biology Karolinska Institute Radiumhemmet, Karolinska Sjukhuset S-104 01 Stockholm 60, Sweden Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205 Department of Pathology and The Cancer Research Center University of North Carolina School of Medicine Chapel Hill, North Carolina 27514 Cancer Biology Program NCI Frederick Cancer Research Center Frederick, Maryland 21701
v
vi Contributors
J. Stephen Haskill Medical University of South Carolina Charleston, South Carolina 29401
Ronald B. Herberman Laboratories of 1mmunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
Howard T. Holden Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
C. Huet Institut de Recherches Scientifiques sur Ie Cancer Villejuif, France
Harry L. Ioachim Department of Pathology Lenox Hill Hospital New York, New York 10021 and Department of Pathology College of Physicians and Surgeons Columbia University New York, New York 10032
Yona Keisari Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
R. S. Kerbel National Cancer Institute of Canada Research Group Division of Cancer Research Department of Pathology Queen's University Kingston, Ontario, Canada K7L 3N6
M. King Institut de Recherches Scientifiques sur Ie Cancer Villejuif, France
Holger Kirchner Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
E. Klein Department of Tumor Biology Karolinska Institute Radiumhemmet, Karolinska Sjukhuset S·104 01 Stockholm 60, Sweden
H. Robson MacDonald Unit of Human Cancer Immunology Lausanne Branch Ludwig Institute for Cancer Research and Department of Immunology Swiss Institute for Experimental Cancer Research 1066 Epalinges·sur· Lausanne, Switzerland
R. Matre Broegelmann Research Laboratory for Microbiology and Department of Microbiology
K. Moore
The Gade Institute University of Bergen Bergen, Norway Paterson Laboratories Christie Hospital and Hn/t Radium Institute Manchester M20 9BX, England
Contributors
M. Moore
Judith L. Pace
v. A. Pollack
Theresa P. Pretlow
Thomas G. Pretlow II
Paolo Puccetti
Maya Ran
Stephen W. Russell
Barbara Schick
Bernard Sordat
Tadayoshi Taniyama
o. T¢nder
Present address: Department of Bacteriology University of Edinburgh Medical School Teviot Place Edinburgh, Scotland
Paterson Laboratories Christie Hospital and Holt Radium Institute Manchester M20 9BX, England
Department of Pathology and The Cancer Research Center University of North Carolina School of Medicine Chapel Hill, North Carolina 27514
Cancer Biology Program NCI Frederick Cancer Research Center Frederick, Maryland 21701
Department of Pathology University of Alabama in Birmingham Birmingham, Alabama 35294
Department of Pathology University of Alabama in Birmingham Birmingham, Alabama 35294
Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
Department of Microbiology The George S. Wise Faculty of Life Sciences Tel A viv University Tel A viv, Israel
Department of Pathology and The Cancer Research Center University of North Carolina School of Medicine Chapel Hill, North Carolina 27514
Department of Cell Biology The Weizmann Institute of Science Rehovot, Israel
Unit of Human Cancer Immunology Lausanne Branch Ludwig Institute for Cancer Research and Department of Immunology Swiss Institute for Experimental Cancer Research 1066 Epalinges·sur-Lausanne, Switzerland
Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205
Broegelmann Research Laboratory for Microbiology and Department of Microbiology The Gade Institute University of Bergen Bergen, Norway
vii
viii
R. R. Twiddy
F. Vanky
Luigi Varesio
S. von Kleist
B. M. Vose
F. Wesenberg
Sandra White
Isaac P. Witz
Margalit Yaakubowicz
National Cancer Institute of Canada Research Group Division of Cancer Research Department of Pathology Queen's University Kingston, Ontario, Canada K7L 3N6 Department of Tumor Biology Karolinska Institute Radiumhemmet, Karolinska Sjukhuset S·104 01 Stockholm 60, Sweden
Contributors
Laboratories of Immunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205 Institute of Tumor Immunology University of Freiburg Freiburg im Breisgau, Germany Department of Tumor Biology Karolinska Institute Radiumhemmet, Karolinska Sjukhuset S-104 01 Stockholm 60, Sweden Present address: Department of Immunology Paterson Laboratories Christie Hospital and Holt Radium Institute Manchester M20 9BX, England Broegelmann Research Laboratory for Microbiology and Department of Microbiology The Gade Institute University of Bergen Bergen, Norway Laboratories of 1mmunodiagnosis and Immunobiology National Cancer Institute Bethesda, Maryland 20205 Department of Microbiology The George S. Wise Faculty of Life Sciences Tel A viv University Tel Aviv, Israel Department of Microbiology The George S. Wise Faculty of Life Sciences Tel A viv University Tel Aviv, Israel
Preface
Because of several valid (and some invalid) reasons, the research field of tumor immunology has been declining in popularity. The Simplistic dogmas, articles of faith, and theories of the late 1960s and early 1970s on the immunological mechanisms of the host-tumor interrelationships have frequently been refuted by some of the new developments in cancer biology, cancer biochemistry, and immunology. Furthermore, some of the conventional assays used to monitor "tumor-host immune relations" did not always reflect the host's true clinical situation or his prognosis. Several approaches to immunological intervention were less successful than expected. In addition, the concept of "immune surveillance," which was basic to many researchers in the field of cancer immunology, seemed to fall apart. Much of the criticism was based on results from solid, well-performed, and well-controlled experiments, but there was also unjust criticism based on ill-conceived and badly performed studies, and on misinterpretations of experimental data.
There are many misconceptions about the tumor-host relationship. It is very often assumed that tumor immunity, as expressed systemically, is truly reflected at the tumor site. Several studies reported in this volume and elsewhere indicate that such is not always the case. Certain immune effectors may be selectively prevented from reaching the tumor site or the close vicinity of the tumor cells because of mechanical or chemical barriers, whereas others may be selectively attracted to the site by chemotaxis or other mechanisms. A selected subpopulation of immune effector components at the tumor site may bring about completely different biological effects from those generated by the more heterogeneous population of peripheral immune components. Thus, a comprehensive understanding of tumor-host relations requires a detailed analysis of immune components found in association with tumors and their functions, as well as of antitumor effector mechanisms operating systemically.
In order to review and critically analyze data obtained from studies of in situ tumor immunity performed independently by several groups, a workshop dedicated to this topic was held in Tel Aviv in June 1978. Many researchers
ix
x Preface
active in this field and most of the contributors to this volume attended the workshop. We wish to thank all the authors for their endeavors.
The studies presented in this volume deal mainly with three topics: (I) The general methodology used to identify, isolate, and assay the functions of tumorderived immune components. This includes some novel approaches and relevant model systems. (2) The biological functions of tumor-associated immune components and their regulation. (3) In situ expressions of immunity in human cancer (which also takes into account the other two topics). In Chapter 1, Drs. Ronald Herberman, Steven Russell, and one of us (I. P. W.) provide a comprehensive introduction to the subsequent chapters by reviewing the main findings, focusing on the unsolved problems, and identifying open questions pertaining to all three topics. We are grateful to them and all the authors for their contributions to this important subject.
Isaac P. Witz M. G. Hanna, Jr.
Contents
Chapter 1
A Review of Data, Problems, and Open Questions Pertaining to in Situ Tumor Immunity
Stephen W. Russell, Isaac P. Witz, and Ronald B. Herberman
1. Problems (Technical and Interpretive) Associated with the Isolation of Immune Effector Cells from Tumors ............... .. . A. Introduction ................................ . B. Morphologic Examination of Tumors ................. 2 C. Tumor Disaggregation ........................... 3 D. Selective Enrichment of Cell Types Recovered from
Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 E. Conduding Remarks ............................ 9
II. The Biological Significance of Tumor-Associated Immune Components .................................... 9 A. Review ..................................... 9 B. Conduding Remarks ............................ 13
III. Difficulties and Significance of Clinical Studies on in Situ Tumor Immunity ...................................... 13 A. Introduction ................................. 13 B. Separation of Tumor Cells from Lymphoid Cells . . . . . . . . . . 14 C. Types of Lymphoid Cells in Human Tumors ............ 15 D. Functional Activities of Immune Factors in Tumors ....... 16 E. Conduding Remarks ............................ 17
IV. References ..................................... 17 A. Problems (Technical and Interpretive) Associated with the
Isolation of Immune Effector Cells from Tumors ......... 17 B. The Biological Significance of Tumor-Associated Immune
Components ................................. 18 C. Difficulties and Significance of Clinical Studies on in Situ Tumor
Immunity ................................... 20
xi
xii
Chapter 2
Separation of Individual Kinds of CeUs from Tumors
Thomas G. Pretlow II and Theresa P. Pretlow
Contents
I. Introduction .................................... 21 II. Composition of Tumors ..... . . . . . . . . . . . . . . . . . . . . . . .. 22
III. Dispersal of Tumors ............................... 23 IV. Separation of Cells ................................ 27
A. Electrophoresis of Cells .......................... 27 B. Sedimentation ................................ 33
V. Criteria for the Documentation of Cell Separation ........... 46 VI. Concluding Remarks ............................... 48
VII. References ..................................... 49
Chapter 3
Immunologic Reactivity of Lymphoid Cells in Tumors
Ronald B. Herberman, Howard T. Holden, LUigi Varesio, Tadayoshi Taniyama, Paolo Puccetti, Holger Kirchner, James Gerson, J. Stephen Haskill, Sandra White, and Yona Keisari
I. Introduction ................................... . II. Reactivity of Immune T Cells ....................... ..
A. Reactivity of Cells in Spleen and Other Lymphoid Organs B. Reactivity of T Cells Isolated from MSV-Induced Tumors ... .
III. Reactivity of Macrophages .......................... . A. Reactivity of Macrophages in Spleen and Peritoneal Cavity .,. B. Reactivity of Macrophages in Tumors ................ .
IV. Reactivity of NK Cells ............................. . A.' Reactivity of NK Cells in Spleen and Blood of
Tumor Bearers ............................... . B. Reactivity of NK Cells in Tumors . . . . . . . . . . . . . . . . . . ..
V. Factors Inhibiting Immune Reactivity .................. . A. Suppressor Cells in Spleen or Peripheral Blood .......... . B. Suppressor Cells and Inhibitory Factors in Tumors ....... .
VI. Conclusions .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. VII. References
Chapter 4
Separation and Characteristics of Tumor-Infiltrating Lymphocytes in Man
E. Klein, F. Vanky, u. Galili, B. M Vose, and M Fopp
61 62 62 63 64 64 65 70
70 71 73 73 73 75 76
I. Introduction .................................... 79
Contents xiii
II. Procedures for the Isolation of Tumor- Infiltrating Lymphocytes 80 A. Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 80 B. Dispersion of Tumor Specimens . . . . . . . . . . . . . . . . . . . .. 81 C. Fractionation of the Tumor Suspension ............... 81 D. Lymphocyte Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 E. Attachment of Tumor- and Blood-Derived T Lymphocytes to a
Variety of Cells ............................... 83 F. Cell Lines ................................... 83 G. Peripheral Blood Lymphocytes (PBL) . . . . . . . . . . . . . . . .. 84 H. Medium .................................... 84 I. Estimation of DNA Synthesis and Autologous Tumor
Stimulation (ATS) Test .......................... 84 1. Autologous Lymphocyte Cytotoxicity (ALC) Test ........ 84
III. Functions of Tumor- Infiltrating Lymphocytes . . . . . . . . . . . . . . 85 A. Presence of SRBC-Rosetting Lymphocytes in the
Biopsy Suspension ............................. 85 B. Separation of Tumor Cells and Lymphocytes ............ 87 C. Suggestive Evidence That at Least Part of the Infiltrating
Lymphocytes Are in the Activated State ............... 94 D. Stimulation of TIL by Autologous Tumor Cells .......... 95 E. Cytotoxicity of TIL against the Tumor Cell Fraction Separated
from the Same Biopsy ........................... 99 F. Relationship between the Reactivity of Blood Lymphocytes in
ATS and ALC Assays with Autologous Tumor Biopsy Cells and the Presence of Lymphocytic Infiltration in the Tumor ..... 100
IV. Discussion ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 101 V. References ..................................... 105
Chapter 5
Intratumor Host Cells of Experimental Rat Neoplasms: Characterization and Effector Function
M Moore and K. Moore
I. Introduction .................................... 109 II. Characteristics of Tumor Infiltration by Host Leukocytes ...... 111
A. Tumor Disaggregation ........................... 111 B. Identification of Intratumor Host Cells ................ 112 C. Host Cell Content of Tumors in F 1 Hybrids . . . . . . . . . . . .. 114 D. Leukocytes within Tumors Serially Transplanted in
Syngeneic Hosts ............................... 115 E. Kinetics of Leukocyte Infiltration ................... 117 F. Factors Controlling Leukocyte Infiltration ............. 119 G. Implications for Tumor Growth in Vivo ............... 121
xiv Contents
III. Tumor-Infiltrating Lymphocytes ..................... " 123 A. Isolation .................................... 123 B. Cytotoxic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . " 124
IV. Intratumor Macrophages ............................ 131 A. Isolation .................................... 131 B. Cytotoxic Activity ............................. 131
V. Discussion .................................... " 135 VI. References ..................................... 138
Chapter 6
Evidence for Mononuclear Phagocytes in Solid Neoplasms and Appraisal of Their Nonspecific Cytotoxic Capabilities
Stephen W. Russell, G. Yancey Gillespie, and Judith L. Pace
I. Introduction .................................... 143 II. Macrophages in Solid Neoplasms ....................... 144
A. Morphological Studies ........................... 144 B. Immune Hemadsorption to Frozen Sections of
Tumor Tissue .... . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 145 C. Cell Suspensions Derived from Disaggregated Neoplasms 147 D. Indirect Means of Associating Macrophages with Tumors .... 151
III. Nonspecific Killing of Tumor Cells by Macrophages Isolated from Solid Neoplasms .............................. 152 A. Assay of Macrophage-Mediated Cytotoxicity ............ 152 B. Evidence for the Mediation of Nonspecific Cytotoxic Effects
by Macrophages Isolated from Solid Neoplasms .......... 153 C. Evidence That Activation of Macrophages is Subverted in
Some Progressively Growing Tumors ................. 155 IV. Technical Considerations in Assaying Cytotoxicity Mediated
by Macrophages Recovered from Tumors ................. 157 A. Population Density of Macrophage Monolayers . . . . . . . . . .. 157 B. Loss of Cytolytic Activity in Vitro .................. , 159 C. Contamination of Macrophage Monolayers with Other
Cell Types ................................... 159 D. Contamination of Tissue Culture Reagents with LPS ....... 160
V. Concluding Remarks ............................... 161 VI. References ..................................... 161
Chapter 7
Mononuclear Cells and IgG Associated with Human Malignant Tissue
O. 'lrpnder, R. Matre, and F. Wesenberg
I. Introduction .................................... 167
Contents
II. Mononuclear Cell Markers in Solid Tumors A. Detection Using Tissue Sections .................... . B. Detection Using Cell Suspensions . . . . . . . . . . . . . . . . . . ..
III. Localization of Fc Receptors in Solid Tumors ............. . IV. Immunoglobulins in Solid Tumors ..................... . V. Relation between Fc Receptors and IgG ................. .
VI. Concluding Remarks .............................. . VII. References .................................... .
Chapter 8
Evidence for Membrane-Bound Antibodies Directed against Antigens Expressed on Tumors
S. von Kleist, M King,and C Huet
xv
168 168 170 171 173 174 174 175
I. Antigens Associated with Human Cancer Tissue ............. 177 II. Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179
A. Passive Hemagglutination ......................... 181 B. Immunofluorescence ............................ 182
III. Analysis of Surgical Tumor Cell Membrane Eluates ........... 182 IV. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 184 V. References ..................................... 186
Chapter 9
Tumor- Localizing Lymphocytotoxic Antibodies
Maya Ran, Margalit Yaakubowicz, Ora Amitai, and Isaac P. Witz
I. Introduction .................................... 191 A. Tumor-Associated Immunoglobulins. . . . . . . . . . . . . . . . .. 191 B. Methodology Used to Study Tumor-Associated
Immunoglobulins .............................. 193 C. Autoantibodies in Tumor Bearers . . . . . . . . . . . . . . . . . . .. 194 D. T-Cell-Related Abnormalities in Tumor Bearers .......... 195
II. Experimental Results .............................. 196 A. Tumor-Bound Lymphocytotoxic Antibodies ............ 196 B. Induction and Selective Tumor Localization of
Lymphocytotoxic Antibodies ...................... 197 C. Partial Identification of the Target Cell and the Target
Antigen for the Tumor-Associated Antilymphocyte Antibody ................................... 200
D. The Nature of Interaction between T ALCA and the Target Cells .................................. 205
III. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 207 IV. References 208
xvi Contents
Chapter 10
Correlations between Tumor Antigenicity, Malignant Potential, and Local Host Immune Response
Harry L. Ioachim
I. Introduction ................................... . II. Malignant Potential and Antigenicity of Tumor Cells ......... .
III. Antigenicity of Tumor Cells and Host Immune Response ...... . IV. The Local Cellular Antitumor Immune Response ........... . V. The Local Humoral Antitumor Immune Response .......... .
VI. Modulation and Selection of Tumor Cells ................ . VII. Summary
VIII. References
Chapter 11
Host Cell Analysis of a Rapidly Metastasizing Mouse Tumor and Derived Low-Metastatic Variant Lines
R. S. Kerbel, R. R. Twiddy, and P. Frost
213 214 217 221 229 232 234 235
I. Introduction .................................... 239 II. Fc Receptors and Tumor Cell Populations . . . . . . . . . . . . . . . .. 240
III. Host Cells and Metastasis ............................ 241 IV. Metastasizing Mouse Tumors . . . . . . . . . . . . . . . . . . . . . . . . .. 242 V. Origin and Properties ofMDAY-D2: A Mouse Tumor
Showing Rapid and Widespread Spontaneous Metastases ....... 243 A. Is MDAY-D2 an H-2 Loss Variant of the
MDAY Tumor? 245 B. Production of Low-Metastatic Variants of the
High-Metastatic MDAY-D2 Tumor ................... 248 C. Host Cell Analysis ofMDAY-D2 versus Low- and High-
Metastatic Variants Obtained by Single Cell Cloning ....... 248 D. Host Cell Analysis of Lectin-Resistant Variants of
MDAY-D2 ................................... 250 VI. Summary
VII. References
Chapter 12
Cellular Basis for Regulation of Tumor Growth
Robert Evans
I. Introduction
251 252
255 II. Accumulation of Host Cells in Tumors ................... 256
Contents xvii
III. Mechanisms Controlling Host Cell Accumulation ............ 259 IV. Tumor-Associated Host Cells, Cytotoxicity, and
Growth Stimulation ............................... 260 V. Cellular Basis of Tumor Regression following Drug Therapy ..... 262
VI. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... " 263 VII. References ..................................... 264
Chapter 13
Immunological Stimulation in Situ: The Acute and Chronic Inflammatory Responses in the Induction of Tumor Immunity
M. C. Hanna, Jr., C. D. Bucana, and V. A. Pollack
I. Introduction .................................... 267 II. Efficacy of BCG Plus Tumor Cell Vaccines for Therapy of
Micrometastatic Malignant Disease . . . . . . . . . . . . . . . . . . . . .. 270 III. Gross Morphology and Measurement of Dermal
Immunization Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 272 IV. Morphological Analysis of Primary and Secondary Immunization
Sites in Tumor-Bearing Guinea Pigs Treated with Immunotherapeutic Vaccines ......................... 274 A. Primary Immunization Sites, Days 1 to 7 ............. " 274 B. Primary Immunization, Days 8 to 26 ................. 277 C. Secondary Immunization Site, Days 1 to 20 . . . . . . . . . . . .. 281
V. Morphological Analysis of Primary and Secondary Immunization Sites in Tumor-Bearing Guinea Pigs Treated with Nonimmunotherapeutic Vaccines ...................... 281 A. BCG Alone .................................. 281 B. LlO Cells Alone ............................... 282 C. 106 BCG + 10 7 LlO Cells . . . . . . . . . . . . . . . . . . . . . . . .. 282
VI. Histological Changes in Superficial Distal Axillary (SDA) Lymph Nodes ................................... 282
VII. Effect of Systemic Immunity on Pulmonary Metastases ........ 284 VIII. Mechanisms of Action of BCG-Tumor Cell Vaccines in the
Generation of Systemic Tumor Immunity ................ . A. The Effect of Surgical Excision of the Dermal Immunization
Site and Regional Lymph Node .................... . IX. Delayed Hypersensitivity Response to Ll 0 Tumor Challenge X. Conclusion .................................... .
XI. References
286
286 288 291 295
xviii Contents
Chapter 14
Tumor Immunity in the Peritoneal Cavity
Gideon Berke and Barbara Schick
I. Introduction .................................... 297 II. Studies of in Situ versus Peripheral Immunity .............. 297
III. Tumor and Allograft Immunity in the Peritoneal Cavity . . . . . . .. 298 A. The Peritoneal Cavity ........................... 298 B. Early Studies on Syngeneic and Allogeneic Systems . . . . . . .. 299 C. Contemporary Studies on Syngeneic Systems ..... . . . . . .. 304
IV. Summary ...................................... 311 V. References ..................................... 312
Chapter 15
The Multicellular Tumor Spheroid: A Quantitative Model for Studies of in Situ Immunity
H. Robson MacDonald and Bernard Sordat
I. Introduction .................................... 317 II. The MTS as a Microtumor ........................... 318
A. Description of Spheroids ......................... 318 B. Growth and Dissemination of EMT6 Spheroids in Vivo . . . . .. 322
III. The MTS as an Experimental Allograft ................... 327 A. Destruction of Spheroids Implanted in Normal or
Immune Allogeneic Mice ......................... 327 B. Characterization of Spheroid-Infiltrating Cells ........... 335 C. Attempts to Identify the Mechanism of Spheroid
Destruction in Situ ............................. 337 IV. Conclusions and Prospects ........................... 338 V. References ..................................... 340
Index 343
