Antagonism of Tumor-Immunity by Chemotherapeutics

dendritic cellSignificant steps forward are being made in immunotherapeutic approaches for treatment of cancer.  Over the past few years, two cancer immunotherapeutics were FDA approved.  In 2010, Dendreon Corporation’s Provenge, an autologous cellular vaccine, was approved for hormone refractory metastatic prostate cancer.  In 2011, Bristol-Myers Squibb’s anti-CTLA4 antibody Ipilimumab, was FDA approved for late stage melanoma.  Recent promising clinical trial results indicate several additional immune modulating therapies are likely to join this prestigious list in the coming years.  In addition, combinations of immune therapies with chemotherapeutics are being tested in clinical trials.  In light of this, it is important to know how chemotherapies interact with the immune system, in order to best generate synergistic effects.

There are multiple ways that chemotherapies may modulate anti-tumor immunity.  Some therapeutics such as anthracyclines induce an immunogenic cell death characterized by release of endogenous danger signals such as HMGB1, that activate antigen presenting cells (APCs) to elicit anti-tumor T cell responses.  Standard apoptosis elicited by a range of other therapeutics however, is often non-immunogenic.  Chemotherapies can induce lymphopaenia which may have both negative and positive effects on anti-tumor immunity, including loss of anti-tumor effector T cells as well as negative regulatory T cells and myeloid derived suppressor cells (MDSC).

In the recent January issue of Nature Medicine, Bruchard et. al., demonstrate that the widely prescribed chemotherapeutic agents, gemcitabine and 5-fluorouracil (5-FU) activated the NLRP3 (NOD-like receptor family, pyrin domain containing-3) inflammasome complex in MDSCs, leading to perturbed anti-tumor immunity and reduced therapeutic effect of these drugs.

The NLRP3 inflammasome is activated in response to damage associated molecular patterns (DAMPs) released during infection with a plethora of pathogens.  NLRP3 activation leads to formation of the multi-protein inflammasome complex that activates caspase-1.  IL-1b is a pro-inflammatory cytokine that is transcribed as an inactive pro-peptide and requires processing by caspase-1 into its active secreted form, and is a major inflammasome effector molecule.

In the study by Bruchard et. al., gemcitabine and 5-FU activated the NLRP3 inflammasome complex in MDSCs, and led to characteristic activation of caspase-1 and IL-1b.   In contrast, the chemotherapeutics Deticene, taxol, oxaliplatin, mitomycin C, and doxorubicin did not activate this pathway.  Cathepsin B release from damaged lysosomes into the cytosol was shown as the trigger of NLRP3 activation by gemcitabine and 5-FU.  Importantly, increased serum concentrations of IL-1b, and enhanced caspase-1 and cathepsin B activity in circulating MDSCs were found colorectal cancer patients one day after 5-FU treatment, validating the relevance of these observations.

Studies on the subset of CD4+ T helper cells that produce IL-17 (TH17) have demonstrated both positive and negative roles for these cells in cancer pathogenesis, and the contexts by which TH17 cells can play opposing roles is unclear.  In this study, IL-1b released by MDSCs treated with 5-FU promoted differentiation of CD4+ T cells into TH17 cells.  5-FU treatment promoted IL-17 production in PBMCs from colorectal cancer human patients as well.  Mice lacking inflammasome components or IL-17 demonstrated enhanced survival when treated with 5-FU.  Thus, in mice, 5-FU elicited TH17 cells play a pro-tumorigenic role.  Whether or not 5-FU elicited TH17 cells also promote tumor growth in human patients is a critical question to be addressed.

Finally, treatment of mice with the soluble form of IL-1Ra blocked the effects of IL-1b and promoted the anti-tumor effects of 5-FU.  Therefore, IL-1b blockade represents a rational immunotherapeutic strategy to enhance the effects of 5-FU and gemcitabine chemotherapies.

In conclusion, this study identified key mechanisms of immune modulation by gemcitabine and 5-fluorouracil in murine models and human cancer patients.  Chemotherapeutics elicit cellular damage by many different mechanisms, and understanding how each drug interacts with the immune system will be important for promoting critical synergy between chemotherapies and anti-tumor immunity.

Further Reading:

Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.  Bruchard M, Mignot G, Derangère V, Chalmin F, Chevriaux A, Végran F, Boireau W, Simon B, Ryffel B, Connat JL, Kanellopoulos J, Martin F, Rébé C, Apetoh L, Ghiringhelli F. Nat Med. 2013 Jan;19(1):57-64.

Immunological aspects of cancer chemotherapy. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Nat. Rev. Immunol. 8, 59–73 (2008).

Dual role of immunomodulation by anticancer chemotherapy.  Shurin MR.  Nat Med. 2013 Jan;19(1):20-2.

Inflammasomes and their roles in health and disease.  Lamkanfi M, Dixit VM. Annu Rev Cell Dev Biol. 2012;28:137-61.

5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell–dependent antitumor immunity. Vincent, J. et al. Cancer Res. 70, 3052–3061 (2010).

Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Suzuki, E., Kapoor, V., Jassar, A.S., Kaiser, L.R. & Albelda, S.M. Clin. Cancer Res. 11, 6713–6721 (2005).

Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies. Apetoh, L., Vegran, F., Ladoire, S. & Ghiringhelli, F. Curr. Mol. Med. 11, 365–372 (2011).