Tumor peptide-MHC Tumor peptide-MHC Primed CTL capableCD28 of killing tumor cells molecularimmunology,ed 9,Philadelphia,2018,Elsevier.) effective in a wide variety of cancers. With all of these caveats, it seems certain that the field of oncology is on the threshold of transformative therapeutic advances, all made possible by careful study of the normal immune response and its myriad variations in cancers.
Tumorcellscanberecognizedbytheimmunesystemasnon-selfanddestroyed.
Antitumoractivityismediatedbypredominantlycell-mediatedmechanisms.TumorantigensarepresentedonthecellsurfacebyMHCclassImoleculesandarerecognizedbyCD8+CTLs.
The different classes of tumor antigens include products ofmutated genes, overexpressed or aberrantly expressed proteins,andtumorantigensproducedbyoncogenicviruses.
Immunosuppressedpatientshaveanincreasedriskfordevelopmentofcancer,particularlytypescausedbyoncogenicDNAviruses.
Inimmunocompetentpatients,tumorsmayavoidtheimmunesystembyseveralmechanisms,includingselectiveoutgrowthof antigen-negative variants, loss or reduced expression ofhistocompatibility molecules, and immunosuppression mediatedbyexpressionofcertainfactors(e.g.,TGF-β,PD-1ligands)bythetumorcells.
•Antibodies that overcome some of these mechanisms ofimmuneevasionarenowapprovedfortreatmentofpatientswithadvancedformsofcancer.
Genomic Instability as an Enabler of Malignancy
The preceding section identified the eight defining features of malignancy, all of which appear to be produced by genetic alterations involving cancer genes. How do these mutations arise? Although humans are awash in environmental agents that are mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively rare outcomes of these encounters. This state of affairs results from the ability of normal cells to sense and repair DNA damage.
The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Individuals born with inherited defects in DNA repair genes are at greatly increased risk for the development of cancer.Defects in three types of DNA repair systems—mismatch repair, nucleotide excision repair, and recombination repair—are presented next. While these discussions focus on inherited syndromes, a point worthy of emphasis is that sporadic cancers often incur mutations in DNA repair genes as well; this in turn enables the accumulation of mutations in cancer genes that contribute directly to development of cancer.