Immunity to Cancers

Chapter 22 Immunity to Cancers





Immune surveillance and protection from cancer


Cancer appears to have engaged the minds of immunologists almost since the beginning of immunology itself. Ehrlich, who opined on all things immunological, believed that the immune system could protect the host from cancer.


Burnet and Thomas refined that idea into the immune surveillance hypothesis of cancer. The hypothesis lived in limbo for several decades, failing to thrive and failing to die, until very recently when the work of Old, Schreiber, and their colleagues demonstrated that mice with a compromised immune status were more prone than immunocompetent mice to develop an array of cancers.


The immune surveillance hypothesis is often regarded as the intellectual underpinning of cancer immunology. Although the hypothesis itself has contributed little to our attempts to treat cancer through immunological means, it has profound implications for understanding the functions of the immune system.




Tumor immunity in the primary host


Entirely unrelated to these two lines of enquiry, the study of cancer immunity saw a revival at the hands of those who were transplanting chemically induced tumors into the many inbred mice that began to be available in the 1950s. These investigators ‘showed “highly successful” immunization against the “transplantable tumors” and expressed great hopes about cancer vaccination’.


In hindsight, these successful immunizations were simply a result of allogeneic differences between tumors and the host strain of mouse, a theme that played a seminal role in definition of the MHC, but had no relevance for cancer immunity.



Nonetheless, amidst the barrage of experiments where MHC-mismatched tumors were transplanted into mice, were the experiments of Ludwik Gross, and later those of Prehn and Main, and of George and Eva Klein, who showed that, even when MHC-matched tumors were used to immunize mice, protection against subsequent tumor growth could be achieved (Fig. 22.1). These studies led to two principles, which have informed much of cancer immunology since and are discussed below.




Cancers elicit protective immunity in the primary and syngeneic host


Mice and rats of a given haplotype can be immunized with irradiated cancer cells that arose in animals of the same haplotype. When they are challenged with live cancer cells, they are able to resist the tumor challenge. The following further observations and deductions have been derived from these results.




It is obviously not possible to test immunogenicity of tumors in humans by the transplantation-challenge experimental paradigm. There is no other reliable method of determining immunogenicity of tumors. It is therefore impossible to comment on the immunogenicity of human tumors. Much of the work in human cancer immunity has been done with melanomas leading to suggestions that, among human tumors, melanomas are particularly immunogenic. This is an erroneous belief – melanomas are simply the easiest human tumors to culture in vitro and hence the easiest to study.




Spontaneous tumors are also antigenically distinct


Cross-reactivity among tumors does occur occasionally. Typically, such cross-reactive immunity has been observed to be significantly weaker than the individually specific antigenicity. Efforts at characterization of such cross-reactive tumor-protective antigens have not made much headway, except in the case of virally induced tumors. In contrast, there has been considerable success in identification of individually distinct antigens.


In addition to these experimental studies, several clinical observations point to the existence of tumor-protective immunity in humans. These include the increased relative risk of cancers in patients who are immunosuppressed because they are kidney transplant recipients (Fig. 22.3) or for a variety of other reasons (Fig. 22.4).






Characterization of tumor antigens


The two broad approaches to the identification of tumor antigens are shown in Figure 22.5 and discussed individually below. Not surprisingly, the approaches have yielded results that are not fully concordant. These differences have helped highlight a fascinating interplay between immunity and tolerance to tumors, discussed below.




Tumor-specific antigens defined by immunization all belong to the family of HSPs


When tumors were biochemically fractionated and individual protein fractions tested for their ability to elicit protective tumor immunity, a number of tumor-protective antigens were identified in diverse tumor models, such as mouse sarcomas, melanomas, colon and lung carcinomas, and rat hepatomas.


Interestingly, regardless of the tumor models used, all antigens were found to belong to the family of proteins known as the heat-shock proteins (HSPs), which:




HSPs must be isolated directly from tumors to be immunologically active


Two aspects of HSP-elicited tumor immunity are notable.



These two observations suggested that HSPs in tumors differ from those in normal tissues and that HSPs in each tumor differ from the same molecules in other tumors.


This conundrum was resolved by the demonstration that the HSP molecules chaperone peptides in a peptide-binding pocket, much as the MHC molecules do, although the structural details of the pockets in HSP and MHC differ (Fig. 22.6). The specificity of immunogenicity derives from the peptides rather than the HSP itself – dissociation of HSP-associated peptides from HSPs abrogate the tumor rejection activity.



HSPs can chaperone many different peptides hence the HSP-chaperoned peptides contain among them any tumor-specific antigenic epitopes present in the tumor cell or the antigenic fingerprint of the tumor from which the HSPs are isolated.image




HSP molecules bind to APCs and target peptides with high efficiency


The HSP molecule itself plays at least two crucial roles other than chaperoning peptides:





It is by this mechanism that immunization with tumor-derived HSPs elicits a CD8 as well as CD4 response against the tumors. In addition, the HSP molecules stimulate the APCs to mediate maturation of DCs and secretion of an array of cytokines that provide the innate milieu for the adaptive response.


Jun 18, 2016 | Posted by in IMMUNOLOGY | Comments Off on Immunity to Cancers

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