Resistance of cancer cells to CTL-mediated immunotherapy. Resistance to targeted anti-cancer therapeutics. Benjamin Bonavida, Salem Chouaib (Eds). Springer International Publishing Switzerland (2015)
During the neoplastic transformation the abnormal expression of some surface, nuclear or cytoplasmic molecules occur. These molecules can represent tumorassociated antigens (TAAs), that following their processing and presentation in association with MHC molecules, can elicit T lymphocyte-mediated anti-tumor responses. These TAAs can be classifies as following:
- Differentiation TAAs. Tumor cells share these antigens with normal cells of the same lineages, however, they are overexpressed in neoplastic cells. This group of TAAs has mainly been found in melanoma and melanocytes, e.g. MART-1/ Melan-A, Gp100, and tyrosinase but also in other epithelial tissues such as the prostate specific antigen (PSA) found in prostate, CEA in CRC and MUC-1 in CRC, lung cancer, mammary cancer etc. .
- Cancer-testis antigens (CTAs), which represent tumor specific TAAs, since their expression in normal tissues is restricted to the testis and placenta. They include the MAGE family proteins (A1, -A2, -A3), NY-ESO-1, NA-17, LAGE, etc. .
- Mutated TAAs: they could arise from point mutations in oncogenes, tumor suppressor genes or genes involved in survival and proliferation pathways .
These molecules represent the potential targets of cancer immunotherapy and since their molecular identification, they have been exploited for several vaccine-based clinical studies for cancer patients. . Targeting TAAs specifically expressed by CSCs could improve the efficacy of cancer vaccines and improve the induction of systemic T cell-mediated immune responses.
The characterization of molecularly known tumor antigens by CSCs has been the objects of a few studies, showing lack or limiting expression of these molecules. Failure in detecting either differentiation, such as MART-1, Gp100, or CT antigens, such as MAGE, NY-ESO-1, or IL-13Ra2 has been documented in CSC from melanoma, GBM or CRC [121–123]. On the other hand, NY-ESO1, Ep-CAM, CEA and SVV-1 were detected in CSCs either from melanoma or CRC, respectively (Table 1.1) [123, 140].
Table 1.1. Expression of TAAs by CSCs
However, none of these TAAs are reported as eliciting efficient T cell-mediated responses against CSCs, suggesting that defective antigen processing and presentation of these antigens, as described in Sect. 1.4, and/or the lack of sufficient expression of these TAAs can prevent the activation of T cell immune responses and their exploitation as target for vaccine based-immunotherapy. Of note, circulating precursor effector cells recognizing a few of these antigens have been found in GBM, melanoma and CRC models, indicating that, though these TAA can elicit immune responses, they cannot be targeting CSCs (Table 1.1) [141–143].
Interestingly, T cell responses against the COA-1 antigen, which is expressed by CSCs, have been isolated in CRC patients, suggesting that this molecule may represent, al least for CRC, a valuable target molecule for T cell-mediated immune responses against CSCs (Table 1.1) .
Further efforts are needed to exploit the mutational profile of CSCs in order to identify candidate TAAs arising from somatic mutations in their genome and to validate their role as novel immunogenic CSC-associated target molecules for immunotherapy.
Although a definitive profile of TAAs expressed by CSCs has not been achieved yet, acquiring a comprehensive analysis of genetic, molecular and immunological features of CSCs may provide relevant information to identify novel highly immunogenic molecules for the specific targeting of CSCs.
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