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Immune Response To Tumors

The inability of the immune response to prevent the development of tumors from single cells stems from several factors relating to tumor composition and the properties of the immune response. Humans are able to generate immune responses against tumor-specific antigens or self-antigens which are aberrantly expressed on tumors, and many tumors are found to be infiltrated by lymphocytes upon histological examination. These tumor immune responses, however, are often ineffective or tolerogenic thereby allowing tumor cells to persist, expand, and eventually escape immune surveillance to form malignant cancers.

A recent model of the immune response to cancer - the cancer immunoediting model - summarizes the ways in which tumor cells and the immune system are thought to interact [1]. In the first phase of tumor progression (elimination) the immune system is able to identify and eliminate nascent tumor cells via CTLs, NK cells, γ:δ T cells, and other immune mechanisms. In the second phase (equilibrium) the immune response begins to fail in that resistant tumor cells develop and proliferate under selective pressures provided by the immune response. These pressures eventually allow certain tumor variants to arise which can escape the local immune response or promote tumor tolerance, enabling the expansion of a tumor from a single cell (escape phase).

One mechanism which enables tumor cells to escape detection is the downregulation of MHC Class I presentation either by a reduction in MHC I production or by disruption of the presentation machinery. Such disruptions prevent the presentation of immunogenic tumor antigens to T cells thereby enabling immune evasion. A lack of antigen presentation makes these cells susceptible to elimination by NK cells and alone is insufficient to account for the immune system's failure to control tumor progression. Another major factor driving this failure is that many immune responses generated against tumors are tolerogenic, leading to immune ignorance of the tumor. This may occur because many tumor antigens are self-antigens which are presented in the absence of co-stimulation. Additionally many tumors develop so as to secrete immunosuppressive cytokines or present negative costimulatory molecules on their surfaces, thereby inactivating local immune responses. For example many tumors produce TGFβ, a cytokine which limits immune proliferation and promotes Treg differentiation. Furthermore many tumors have been identified expressing negative costimulatory molecules such as PD-1, PD-L1, and CTLA4 which suppress or significantly increase thresholds for T cell activation. A number of additional tumor adaptations have been identified such as IDO production or the secretion of collagen to form physical barriers against lymphocyte infiltration.

While the immune system is well adapted to detecting and eliminating many potentially deleterious insults, it operates at a disadvantage when detecting developing tumors which primarily present self antigens, as the immune system is organized to limit self-reactivity. Many aberrant cells are detected and eliminated, however a few cells are able to divide and mutate under the selective pressures provided by the immune system. This ultimately allows certain single tumor cells to develop which have evolved to take advantage of normal immune physiology in order to to escape the immune response, thus leading to cancer progression.

Assessment of Tumors

High throughput screening would enable you to begin to address whether or not primary tumors carry all the necessary mutations to metastasize. One experimental approach would be to identify a primary tumor in a mouse model (either an induced tumor or a tumor-prone mouse strain). The cells of this primary tumor should then be sequenced and assessed via DNA/RNA microarrays for patterns of gene expression. The tumor should then be divided and transplanted into a large number (~1000) of genetically identical mice, and allowed to grow to the point of metastasis. Metastatic tumors should then be isolated from these mice, sequenced, assessed for RNA/DNA expression patterns, and these patterns should be compared to the primary tumor. If the primary tumor contained all the necessary metastatic driver mutations then the range of polymorphisms in the metastasized tumors would be expected to be randomly distributed across various genes. If, however, specific mutations were present at significantly high frequencies then they would be candidates for driver mutations suggesting that the primary tumor lacked metastatic potential without further mutation. To further support this result, candidate driver mutation genes could be knocked out in samples of the initial tumor via siRNA in order to determine whether or not these tumors are still capable of metastasizing.

As an alternative to analysis of a specific primary tumor and its metastatic progeny, a large number of a single type of tumor (both primary and metastatic) could be isolated from mice and sequenced. The progression of these tumors could be monitored in these mice over time to identify which primary tumors successfully undergo metastasis. If there were specific mutations common to the majority of metastasized tumors but not to the majority of primary tumors then this would support the idea that primary tumors need to undergo mutation to metastasize. If, however, these candidate driver mutations are common to the primary tumors which most readily metastasize then this would support the idea that primary tumors which do go on to metastasize do not require further transformation to achieve this deleterious effect.

Diseases which are the result of balancing selection will have elevated frequency in specific population in which they were originally selected for relative to the general population. To identify candidate diseases that are the result of balancing selection, epidemological data should be gathered indicating disease frequency in specific racial, ethnic, and/or religious populations. Any diseases which are represented at a significantly elevated level in specific populations are candidates for diseases stemming from balancing selection, as one would normally expect any high-frequency disease causing genes to have been eliminated via purifying selection from the population over time.

For any diseases which are represented at significantly higher levels in a specific population, a large number of members of that population should have their genomes sequenced as part of a genome-wide association study. Individuals should be grouped into those within the population known to have the disease and those known not to have the disease. If the disease were 100% penetrant in homozygous individuals, then pedigrees could be constructed in order to determine which individuals are heterozygous carriers of the disease-associated gene(s), allowing for comparison between +/+, +/*, and */* individuals. Polymorphisms which are found at a significantly higher level in diseased individuals and disease +/* carriers relative to non-diseased individuals are candidates for the loci mediating disease. As the population is likely to be somewhat genetically homogenous, there will be reduced genetic drift within the population relative to the general population thereby improving the chances of identifying mutated genes/loci responsible for the disease in question. Once candidate polymorphisms have been identified, their frequency should be compared to the general population. If these mutations are associated with disease in homozygous individuals in the effected population, but are present at an elevated frequency relative to the general population then there is good chance that these polymorphisms are the result of balancing selection due to some conferred heterozygote advantage in the population in which they is prevalent.

The availability of 100,000 control human exomes provides an exceptionally powerful experimental system which can be used to identify all candidate haploinsufficient lethal genes. Haploinsufficient genes are those which require the presence of two functional copies for an organism to survive. Accordingly, one would expect there to be virtually no polymorphisms in the general population within these haploinsufficient lethal genes, and any polymorphisms which do occur must leave the gene functionally intact thus limiting the potential number of mutations. The most effective way to make use of these 100,000 exomes would be to sequence all of them and compare these sequences in order to ascertain the frequencies of single nucleotide polymorphisms within all genes. Genes which contain a statistically negligible number of polymorphisms across this diverse exome population are likely candidates for haploinsufficient lethality. These genes are not definite haploinsufficient lethal genes, as they may be very closely linked to conserved sequences or they may simply by chance not present with any polymorphisms within the 100,000 exomes sampled, however they is a high probability that at least some of them will fulfill the criteria for haploinsufficient lethality. In this way the exome data can be used to simultaneously identify myriad potentially novel disease-related genes.

References

1. Schreiber RD, Old LJ, Smyth MJ. Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion. Science. 331 (6024): 1565-1570


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