304
Immunology Today, vol. 4, No. 11, 1983
Tumour
immunology
Immunological manoevres should not be dismissed from Adrian Robins Immunological studies of cancer have diverse objectives, ranging from identifying the relationship of antigenic change in tumour cells to the process of carcinogenesis, through detailed analysis of the complex regulatory and effector mechanisms operative in the response to experimental tumours of proved antigenicity, to a pragmatic interest in manipulating immunological mechanisms for therapeutic purposes. G. Klein (Stockholm) presented an appraisal of the role of sequential genetic changes involved in the natural history of developing tumour and concluded that, with the exception of DNA-virusinduced tumours (described as the last citadel for immune surveillance and viral oncogenesis), activation of cellular oncogenes need not cause the expression of tumour antigens which could provide a target for surveillance. As O. Stutman (New York) pointed out when considering the possible role of N K cells in tumour immunity, the failure of a mechanism to recognize and eliminate tumour in its early development does not necessarily mean that the mechanism plays no part in the control of established primary tumour, or its metastatic spread. These conclusions must be considered in any discussion of the recognition events involved in the implementation of the tumour immune response and when asking which aspect of the response is most important in the rejection process. Thus approached, from the 'effector cell end', this question pmvides a variety of answers depending on the system investigated. For example, M. Giovarelli and G. Forni (Turin) described a system in which effector cells from mice bearing chemically induced tumour had strong antitumour effects after in-vitro restimulation; cytotoxic activity could be removed from these populations by absorption on tumour-cell monolayers, but this did not affect the in-vivo efficacy of the cells. In other systems, cell populations apparently lacking cytotoxicity have demonstrable antitumour effects on transfer, but function synergistically with cytotoxic precursor populations. Whether a single class of cytotoxic effector cells is of primary importance in the collaboration with helper cells remains open: the importance of helper cells, and of determinants which stimulate them, seems clear. The finding that cytotoxic effector cells can be generated against human
tumours when exogenous lymphokines are provided could be interpreted as a demonstration that determinants recognized by cytotoxic T-cell (CTL) precursors are present on tumour cells, but that suitable helper determinants are lacking. Supplementation of helper responses in vivo was illustrated in experimental systems by T. Harnaoka (Osaka), who uses anti-hapten responses to induce tumour rejection. These manipulations are successful only if the anti-hapten suppressor response is controlled, but the potential of this approach was convincingly demonstrated by the induction of regression of primary methylcholanthrene-induced tumours in mice by an anti-trinitrochlorobenzene response. The importance of suppression in the response to immunogenic tumours was reiterated by R . J . North (Saranac Lake, NY), who reported the development and persistence of suppressor cells induced by progressively growing tumour. Interestingly, the removal of a large tumour mass was not sufficient to relieve suppression. If human tumours are potentially immunogenic, this would indicate that tumour 'debulking' may not be sufficient to allow the putative response to operate. Also of interest was the demonstration that in two mouse systems, tumour-induced suppression was transferred effectively by Lyl+2 cells. This may indicate that this cell is related to the suppressor-inducer cell identified in other systems, and also has implications for the interpretation of experiments for phenotyping cells active in the transfer of tumour immunity.
No clear conclusion could be drawn about the general importance of natural killer (NK) cells in turnour control. They appear to be relevant in some circumstances, particularly in the control of metastasis, but many examples were provided where manipulation of NK cells did not result in a change in tumour incidence. As R. Herberman (Frederick) pointed out, however, factors such as the selective depression of one mechanism, which may allow alternative mechanisms to operate, make these experiments difficult to interpret. The overall impression generated by the tumour immunology studies presented at Kyoto is that one should not be too quick to dismiss the potential of immunological maneouvres in cancer detection and treatment. This may be especially true of non-specific immunostimulation, where, for example, Y. Yamamura (Osaka) presented very encouraging results on the experimental and clinical use ofNocardia CWS. It seems possible that useful results may be achievable using a judicious combination of specific and non-specific manipulation, perhaps involving the supply of lymphokines, transfer of sensitized cells, control of suppression, systemic immunomodulation, and use of monodonal antibodies. In practical terms, we are still far from realizing this objective.
R. A. Robins is in the CancerResearch Campaign Laboratories, Nottingham Universi~, Nottingham NG7 2RD, UK.
Autoimmune
disease
T-cell balance in organ targets from Yi-chi Kong There is now a lot of evidence that T cells reactive to autoantigens initiate organspecific autoimmune diseases. The existence of MHC-linked, autoreactive T cells responsive to organ-specific antigens suggests that autoimmune damage is unlikely often to be caused by a T-cellbypass mechanism involving a polyclonal B-cell activator or cross-reactive (altered) autoantigen. Much of this evidence has emerged from detailed studies on experimental autoimmune thyroiditis (EAT) in mice, which have located the
immune response gene for thyroglobulin (Tg) at the I-A subregion, with the D-end modifying the severity of thyroid damage, and have shown that T-cell subsets from affected mice not only proliferate in vitro during restimulation with Tg but differentiate into cytotoxic T cells that are K- and D-region restricted. Such autoreactive T cells are held in check by Tg-specific suppressor mechanisms which can be activated by exogenous or hormonally released Tg. Thus, autoimmune disease results when the clonal
Immunology Today, vol. 4, No. 11, 1983
Tumour
immunology
Immunological manoevres should not be dismissed from Adrian Robins Immunological studies of cancer have diverse objectives, ranging from identifying the relationship of antigenic change in tumour cells to the process of carcinogenesis, through detailed analysis of the complex regulatory and effector mechanisms operative in the response to experimental tumours of proved antigenicity, to a pragmatic interest in manipulating immunological mechanisms for therapeutic purposes. G. Klein (Stockholm) presented an appraisal of the role of sequential genetic changes involved in the natural history of developing tumour and concluded that, with the exception of DNA-virusinduced tumours (described as the last citadel for immune surveillance and viral oncogenesis), activation of cellular oncogenes need not cause the expression of tumour antigens which could provide a target for surveillance. As O. Stutman (New York) pointed out when considering the possible role of N K cells in tumour immunity, the failure of a mechanism to recognize and eliminate tumour in its early development does not necessarily mean that the mechanism plays no part in the control of established primary tumour, or its metastatic spread. These conclusions must be considered in any discussion of the recognition events involved in the implementation of the tumour immune response and when asking which aspect of the response is most important in the rejection process. Thus approached, from the 'effector cell end', this question pmvides a variety of answers depending on the system investigated. For example, M. Giovarelli and G. Forni (Turin) described a system in which effector cells from mice bearing chemically induced tumour had strong antitumour effects after in-vitro restimulation; cytotoxic activity could be removed from these populations by absorption on tumour-cell monolayers, but this did not affect the in-vivo efficacy of the cells. In other systems, cell populations apparently lacking cytotoxicity have demonstrable antitumour effects on transfer, but function synergistically with cytotoxic precursor populations. Whether a single class of cytotoxic effector cells is of primary importance in the collaboration with helper cells remains open: the importance of helper cells, and of determinants which stimulate them, seems clear. The finding that cytotoxic effector cells can be generated against human
tumours when exogenous lymphokines are provided could be interpreted as a demonstration that determinants recognized by cytotoxic T-cell (CTL) precursors are present on tumour cells, but that suitable helper determinants are lacking. Supplementation of helper responses in vivo was illustrated in experimental systems by T. Harnaoka (Osaka), who uses anti-hapten responses to induce tumour rejection. These manipulations are successful only if the anti-hapten suppressor response is controlled, but the potential of this approach was convincingly demonstrated by the induction of regression of primary methylcholanthrene-induced tumours in mice by an anti-trinitrochlorobenzene response. The importance of suppression in the response to immunogenic tumours was reiterated by R . J . North (Saranac Lake, NY), who reported the development and persistence of suppressor cells induced by progressively growing tumour. Interestingly, the removal of a large tumour mass was not sufficient to relieve suppression. If human tumours are potentially immunogenic, this would indicate that tumour 'debulking' may not be sufficient to allow the putative response to operate. Also of interest was the demonstration that in two mouse systems, tumour-induced suppression was transferred effectively by Lyl+2 cells. This may indicate that this cell is related to the suppressor-inducer cell identified in other systems, and also has implications for the interpretation of experiments for phenotyping cells active in the transfer of tumour immunity.
No clear conclusion could be drawn about the general importance of natural killer (NK) cells in turnour control. They appear to be relevant in some circumstances, particularly in the control of metastasis, but many examples were provided where manipulation of NK cells did not result in a change in tumour incidence. As R. Herberman (Frederick) pointed out, however, factors such as the selective depression of one mechanism, which may allow alternative mechanisms to operate, make these experiments difficult to interpret. The overall impression generated by the tumour immunology studies presented at Kyoto is that one should not be too quick to dismiss the potential of immunological maneouvres in cancer detection and treatment. This may be especially true of non-specific immunostimulation, where, for example, Y. Yamamura (Osaka) presented very encouraging results on the experimental and clinical use ofNocardia CWS. It seems possible that useful results may be achievable using a judicious combination of specific and non-specific manipulation, perhaps involving the supply of lymphokines, transfer of sensitized cells, control of suppression, systemic immunomodulation, and use of monodonal antibodies. In practical terms, we are still far from realizing this objective.
R. A. Robins is in the CancerResearch Campaign Laboratories, Nottingham Universi~, Nottingham NG7 2RD, UK.
Autoimmune
disease
T-cell balance in organ targets from Yi-chi Kong There is now a lot of evidence that T cells reactive to autoantigens initiate organspecific autoimmune diseases. The existence of MHC-linked, autoreactive T cells responsive to organ-specific antigens suggests that autoimmune damage is unlikely often to be caused by a T-cellbypass mechanism involving a polyclonal B-cell activator or cross-reactive (altered) autoantigen. Much of this evidence has emerged from detailed studies on experimental autoimmune thyroiditis (EAT) in mice, which have located the
immune response gene for thyroglobulin (Tg) at the I-A subregion, with the D-end modifying the severity of thyroid damage, and have shown that T-cell subsets from affected mice not only proliferate in vitro during restimulation with Tg but differentiate into cytotoxic T cells that are K- and D-region restricted. Such autoreactive T cells are held in check by Tg-specific suppressor mechanisms which can be activated by exogenous or hormonally released Tg. Thus, autoimmune disease results when the clonal
