The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy

Abstract

Preclinical studies have revealed an unexpected ability of the immune system to contribute to the success of chemotherapy and radiotherapy. Anticancer therapies can trigger immune system activation by promoting the release of danger signals from dying tumor cells and/or the elimination of immunosuppressive cells. We have, however, recently discovered that some chemotherapies, such as 5-fluorouracil and gemcitabine, exert conflicting effects on anticancer immune responses. Although 5-fluorouracil and Gem selectively eliminated myeloid-derived suppressive cells in tumor-bearing rodents, these chemotherapies promoted the release of IL-1β and the development of pro-angiogenic IL-17-producing CD4 T cells. The ambivalent effects of chemotherapy on immune responses should thus be carefully considered to design effective combination therapies based on chemotherapy and immune modulators. Herein, we discuss how the initial findings underscoring the key role of the immune system in mediating the antitumor efficacy of anticancer agents could begin to translate into effective therapies in humans.

Keywords::

• 5-fluorouracil
• anticancer immunity
• inflammasome
• immunomodulation
• immunosuppression
• myeloid-derived suppressor cell

Financial & competing interests disclosure

F Ghiringhelli is supported by grants from the Ligue Nationale Contre le Cancer, the Fondation de France, the Institut National du Cancer, the Association pour la recherche sur le cancer, the Conseil Régional de Bourgogne and the FEDER. L Apetoh is supported by grants from the Fondation de France, the Conseil Régional de Bourgogne, the FEDER, the Agence Nationale de la Recherche (ANR-10-PDOC-014-01), the Ligue Régionale contre le cancer Comité Grand-Est and the European Community (Marie Curie Fellowship PCIG10-GA-2011-303719). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Challenging the presiding view that anticancer agents were immunosuppressive, early studies in the seventies have proposed that the efficacy of anticancer agents relied on host immunity.

• Tumor cell death triggered by chemotherapy can set off anticancer immune responses.

• The immunogenicity of tumor cell death induced by chemotherapy relies on the cell surface exposure of calreticulin, high mobility group box 1 protein release, induction of autophagy and ATP release.

• Some chemotherapies can also relieve immunosuppression by eliminating immunosuppressive cells such as Treg cells and myeloid-derived suppressor cells.

• Combination therapies coupling chemotherapies and immunomodulators feature synergistic anticancer effects.

• The immunomodulatory agent ipilimumab has proven its efficacy for the treatment of metastatic melanoma and is now routinely implemented in clinical practice.

Notes