Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8+ T cells in vivo

Abstract

Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNγ and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.

Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence

“…Interestingly, CDDP’s ability to upregulate MHC class I expression may not be limited to just tumor cells but, as Jackaman et al illustrated, CDDP may also increase MHC class I expression on antigen presenting cells (APCs) (14). In a murine mesothelioma model, the authors treated tumor-bearing mice with either two doses of CDDP or a PBS control and demonstrated that tumor-associated CD11c + dendritic cells from mice treated with CDDP had greater MHC class I expression than did the dendritic cells from control mice (14).…”

A review of the importance of immune responses in luminal B breast cancer

“…This may be via expression of HMG proteins that bind platinum complexes to cause repair shielding and initiate apoptosis. 23 We have shown that while cisplatin only slightly enhances in vivo presentation of dominant tumor antigens to T cells in draining lymph nodes, both cisplatin and gemcitabine expand the CTL response to weaker subdominant tumor epitopes 24 ; a feature that may be key to tumor destruction as immune tolerance mechanisms are likely to delete responses to dominant epitopes. Moreover, immune-relevant metagene analyses have shown a significant positive correlation with response rates for BC to chemotherapy, in particular to a CXCL13-centered metagene signature reflecting the intratumoral presence of activated IFNg-producing T cells.…”

L’immunothérapie au service de la chimiothérapie, de nouvelles avancées

“…Ce changement de répertoire pourrait résulter de différences d'activation des lymphocytes T, d'affinité des TCR (T cell receptor), d'expression de molécules inhibitrices, etc. Jackaman et al ont par ailleurs montré que la chimiothérapie peut révéler des antigènes tumoraux sous-dominants contre lesquels une réponse n'est induite qu'après un traitement [11]. L'ensemble de ces observations suggèrent une action directe (indépendante de la présentation des antigènes tumoraux) du traitement chimiothérapeutique sur l'activation des lymphocytes T. Chez des patients atteints de mélanome, ces chimiokines sont également augmentées dans les lésions qui sont sensibles à la chimiothérapie [12].…”