Immunology and immunotherapy of colorectal cancer
Introduction
Like most epithelial solid tumours, colorectal carcinoma has long been considered poorly immunogenic and substantially refractory to immunotherapy. This opinion was based on indirect data from: (a) epidemiological studies on lack of spontaneous regression of cancer; (b) in vitro studies on tumour infiltrating lymphocytes (TIL); (c) a first generation of clinical trials of immunotherapy in colorectal cancer patients. In fact, while in known immunogenic tumours, such as melanoma, primary lesions can sporadically undergo spontaneous regression associated with tumour infiltration by immune effectors (3–7% of cases), in colorectal carcinoma spontaneous regression is only exceptionally observed, and does not appear to be associated with an immune response [1], [2], [3]. Again, in contrast with data collected in melanoma, in vitro studies performed on bulk TIL cultures purified from colorectal carcinomas failed to demonstrate substantial lytic activity against autologous cancer cells [4], [5]. Moreover, classical immunotherapeutic interventions known to be active against melanoma, such as systemic administration of cytokines (IL-2, INF-α) or adoptive transfer of autologous lymphocyte effectors (LAK, lymphokine-activated killer cells; TIL), have proved ineffective in colorectal tumours [5], [6], [7], [8].
During the last decade, however, continuous progress in the molecular characterisation of T cell-defined tumour associated antigens (TAA) and in methods allowing detection of antigen-specific T cell responses have slowly modified the scientific community's perspective on this issue. Indeed, several different lines of evidence indicate today that also epithelial solid tumours may express TAA recognised by T cells, and that anti-tumour immune responses indeed may take place in colorectal cancer patients, influencing patient prognosis and shaping the tumour immunological profile (see below). The aim of this review is to pool old and new data from basic studies and from clinical trials, in an attempt to critically explore colorectal carcinoma immunology and envisage a rational development of new immunotherapeutic approaches directed against this disease.
Section snippets
Histopathological studies
One classical way to evaluate if anti-tumour immune responses are taking place in vivo in cancer patients, and can influence the natural history of the disease, is to perform histopathological evaluation of surgically resected tumour lesions looking for immune effectors within tumour tissue, and trying to correlate their presence with patient prognosis. In melanoma, histopathological studies have shown that spontaneously regressing tumours are heavily infiltrated by T cells [9], [10] and that T
HLA molecules on colorectal carcinoma
Antigen recognition by T cells is dependent on the expression of HLA molecules by target cells. The role of HLA is to bind small antigenic peptides produced by the active enzymatic degradation of proteins and to present them on the cell surface so that they can be screened and recognised by the TCR. HLA molecules belong to two main classes, class I and class II, and have distinct structural and functional features. As a general rule, class I HLA are involved in antigen recognition by CD8 αβ T
T lymphocyte-defined tumour antigens able to evoke an immune response in colorectal cancer patients
It is now well accepted that tumour cells can express proteins able to activate the immune system and to become targets for a T cell-mediated response. The bulk of information regarding the relationship between tumour cells and the immune system of cancer patients are derived from the in vivo and in vitro immunological studies performed with melanoma [92]. These studies provide immunologists with a perspective on the nature of T cell-defined TAA not only in melanoma but in general in many other
Clinical trials of immunotherapy
Hitherto, immunotherapy against colorectal cancer has met with limited success. Classical approaches developed for the treatment of melanoma, such as adoptive immunotherapy with LAK or TIL and systemic administration of cytokines like IL-2 and INF-α, have proved ineffective in colorectal carcinoma. However, continuous scientific and technological developments both in monoclonal antibody (mAb) and in vaccine design have today prompted a new wave of clinical trials, in some cases with encouraging
Summary
A critical evaluation of data acquired over the last several years has provided some support for the hypothesis that the immune system can affect colorectal cancer growth and metastatic dissemination. Among the most convincing lines of evidence supporting this hypothesis are the finding that CD8+ T cell intra-epithelial infiltration of primary tumours represents a strong favourable prognostic factor, as well as the frequent loss of class I HLA by tumour cells. Molecular characterisation of the
Reviewers
Professor Rolf Kiessling, Department of Oncology–Pathology, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Markus Maurer, M.D., Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-Universität Mainz, Hochhaus am Augustusplatz, D-55101 Mainz, Germany.
Paul F. Robbins, M.D., NIH/National Cancer Institute, Building 10, Room 2B42$10 Centre DR, Bethesda MD 20892-1502, USA.
Acknowledgements
Piero Dalerba is a research fellow of the Fondazione Italiana per la Ricerca sul Cancro (Milan). The work of the Unit directed by Giorgio Parmiani was supported by the Italian Association for Cancer Research (Milan), the EC Grant (QLK3-1999-00064) and the Italian Ministry of Health (Rome). The editorial assistance of Grazia Barp is gratefully acknowledged.
Giorgio Parmiani was born in 1938, M.D. in 1964 at the University of Milan and specialised in Oncology in 1976. Dr Parmiani began his career in 1967 at the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan (INT). He was trained in tumour immunology by Richard T. Prehn at the Institute for Cancer Research of Philadelphia (1969–1970), and then continued his career at INT. He is now Deputy Scientific Director of the INT and Head of the Unit of Immunotherapy of Human Tumours. Since
References (243)
Spontaneous regression of cancer
Cancer Treat. Rev.
(1996)- et al.
Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma
J. Invest. Dermatol.
(1991) - et al.
From Dukes through Jass: pathological prognostic indicators in rectal cancer
Hum. Pathol.
(1994) - et al.
Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis
Am. J. Pathol.
(2001) - et al.
Survival for colon and rectal cancer in a population-based cancer registry
Eur. J. Cancer
(1996) - et al.
Prognostic significance of eosinophils and mast cells in rectal cancer: findings from the National Surgical Adjuvant Breast and Bowel Project (protocol R-01)
Hum. Pathol.
(1989) - et al.
Stromal eosinophilia in colonic epithelial neoplasms
Am. J. Gastroenterol.
(2000) - et al.
Quantification of colonic lamina propria cells by means of a morphometric point-counting method
Gastroenterology
(1988) - et al.
Inflammation and cancer: back to Virchow
Lancet
(2001) - et al.
The origin and function of tumor-associated macrophages
Immunol. Today
(1992)
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
Cell
High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability
Am. J. Pathol.
Histopathological identification of colon cancer with microsatellite instability
Am. J. Pathol.
Selection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas
Curr. Biol.
Analysis of TCR usage in human tumors: a new tool for assessing tumor-specific immune responses
Immunol. Today
MHC antigens and tumor escape from immune surveillance
Adv. Cancer Res.
Antitumor immunity at work in a melanoma patient
Adv. Cancer Res.
Natural history of HLA expression during tumour development
Immunol. Today
Expression of class II molecules on intestinal epithelial cells in humans. Differences between normal and inflammatory bowel disease
Gastroenterology
T cells in inflammatory bowel disease: protective and pathogenic roles
Immunity
Characterisation of tumour infiltrating lymphocytes and correlations with immunological surface molecules in colorectal cancer
Eur. J. Cancer
Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma
Biochem. Biophys. Res. Commun.
Spontaneous regression of colon carcinoma
Natl. Cancer Inst. Monogr.
Spontaneous resolution of histologically proven liver metastases from colorectal cancer
Br. J. Surg.
Patterns of human tumor-infiltrating lymphocytes in 120 human cancers
Arch. Surg.
Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer
J. Clin. Oncol.
A phase II clinical trial of interleukin-2 and lymphokine-activated killer cells in advanced colorectal carcinoma
J. Immunother.
Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer
J. Clin. Oncol.
Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol C-05
J. Natl. Cancer Inst. USA
Evidence for in situ amplification of cytotoxic T-lymphocytes with antitumor activity in a human regressive melanoma
Cancer Res.
Model predicting survival in stage I melanoma based on tumor progression
J. Natl. Cancer Inst. USA
Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma
Cancer
Lymphocytic infiltration and survival in rectal cancer
J. Clin. Pathol.
Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer
J. Pathol.
CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer
Cancer Res.
Total rectal resection and complete mesorectum excision followed by coloendoanal anastomosis as the optimal treatment for low rectal cancer: the experience of the National Cancer Institute of Milano
Ann. Surg. Oncol.
Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue
J. Pathol.
American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group
Cancer
Eosinophil infiltration of human colonic carcinomas as a prognostic indicator
Cancer Res.
Prognostic influence of tumor-associated eosinophilic infiltrate in colorectal carcinoma
Cancer
Geographic variations in eosinophil concentration in normal colonic mucosa
Mod. Pathol.
Mast cells in colorectal neoplasias and premalignant disorders
Dis. Colon Rectum
Inflammatory cells and cancer: think different
J. Exp. Med.
Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy
J. Exp. Med.
Elevation of infiltrating mononuclear phagocytes in human colorectal tumors
J. Natl. Cancer Inst. USA
Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis
Br. J. Cancer
Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells
J. Natl. Cancer Inst. USA
Angiogenin expression in human colorectal cancer: the role of focal macrophage infiltration
Clin. Cancer Res.
Dendritic cell infiltration in colon cancer
J. Immunother.
Cytotoxic T lymphocyte therapy of cancer and tumor escape mechanisms
Semin. Cancer Biol.
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Giorgio Parmiani was born in 1938, M.D. in 1964 at the University of Milan and specialised in Oncology in 1976. Dr Parmiani began his career in 1967 at the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan (INT). He was trained in tumour immunology by Richard T. Prehn at the Institute for Cancer Research of Philadelphia (1969–1970), and then continued his career at INT. He is now Deputy Scientific Director of the INT and Head of the Unit of Immunotherapy of Human Tumours. Since 1998 he is also Director of the Ph.D. Course in Molecular Oncology of INT held in collaboration with the Open University of London. As expert in the field of immunology and immunotherapy of tumours, Dr Parmiani performed studies on experimental and human systems and promoted and carried out many translational clinical protocols. His scientific activity is recognisable by the participation into many important meetings as invited speaker and by the over 400 publications in the most important international journals.
Piero Dalerba was born in Milan (Italy) in 1970 and graduated as M.D. in 1995 at the State University of Milan. He was trained as a medical oncologist in several Italian institutions (Ospedale San Raffaele in Milan; University Hospital in Padua) and finally completed his specialisation course in oncology in the year 2000 at the Istituto Nazionale Tumori in Milano, where he is now a Research Fellow in the Unit of Immunotherapy of Human Tumours, directed by Dr Giorgio Parmiani. Alongside clinical practice, he was also trained in basic research in several Italian laboratories, focusing on gene therapy (TIGET, Milan), chemokine receptors (Istituto ‘Mario Negri’, Milano) and tumour immunology (University Department of Oncology, Padua; Istituto Nazionale Tumori, Milan). In 2001 he was awarded a 3-year research fellowship by the Italian Foundation for Cancer Reserach (FIRC) for a research project entitled ‘Identification and molecular characterisation of new T cell-defined tumour antigens in colorectal cancer’.