MHC class I-restricted epitope spreading in the context of tumor rejection following vaccination with a single immunodominant CTL epitope

Abstract

Epitope spreading is a process whereby epitopes distinct from and non‐cross‐reactive with an inducing epitope become targets of an evolving immune response. This phenomenon has been associated most notably with the progression of naturally occurring or experimentally induced chronic autoimmune diseases. We have investigated the potential occurrence of epitope spreading in the context of antitumor cytotoxic T cell (CTL) responses using chicken ovalbumin (OVA) as a model antigen. Our results indicate that following rejection of OVA‐expressing EG.7 tumor cells effectuated by a CTL response which is induced against the MHC class I‐restricted immunodominant epitope OVA257 – 264, there occurs intramolecular diversification of the CTL response to two additional OVA‐derived epitopes, OVA176 – 183 and OVA55 – 62, as well as intermolecular spreading to other endogenous tumor‐derived determinants. It seems that CTL‐mediated tumor cell destruction in vivo favors cross‐presentation of additional epitopes with the consequent activation of additional tumor‐reactive lymphocytes. The process of epitope spreading in that context has obvious important implications for the design of antigen‐specific antitumor immunotherapies.

Short-Term Kinetics of Tumor Antigen Expression in Response to Vaccination

“…In addition, we cannot exclude that the patients may have developed an immune response to the other MDA whose expression was found to be reduced. Therefore, broader effects of systemic IL-2 administration or epitope spreading in the tumor microenvironment might have been at the basis of the extended loss of MDA (37,38). However, this explanation would leave unanswered the question of why epitope spreading would preferentially affect MDA compared with CT, whose expression was not affected in responding lesions.…”

Unmasking cryptic epitopes after loss of immunodominant tumor antigen expression through epitope spreading

“…11,26,27 Pre-clinical models suggest that epitope spreading occurs in association with tumor rejection after vaccination with a single immunodominant CTL epitope. 15 Thus, under immunemediated perturbations of the tumor microenvironment, an additional signal is induced that complements the weak signal ordinarily provided by TA-bearing cancer cells. 2 Antigen spreading, however, has never been demonstrated to occur in response to anti-cancer treatments in humans.…”

“…14 Finally, MAGE-12-specific CTL could have risen in response to vaccine-induced modifications of the tumor environment. 15 These hypotheses were tested by this study.…”

Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance

“…Interestingly, there is a paucity of such data for CD8 ϩ T cells, which tends to support our conclusions. Nevertheless, MHC I-restricted epitope spreading has been reported for responses to some tumors (40)(41)(42). Our findings suggest that such responses should occur only if the tumor itself is able to supply sustained adjuvant signals, which could be the case for some tumors.…”