Antagonism of Tumor-Immunity by Chemotherapeutics
Cancer Immunotherapy Is Advancing Fast
Cancer immunotherapy has made major strides in recent years. Two cancer immunotherapeutics have won FDA approval so far:
- 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 approved for late-stage melanoma.
Promising clinical trial results suggest several more immune-modulating therapies will join this list in the coming years.
Researchers are also testing combinations of immune therapies with chemotherapeutics in clinical trials. This makes it important to understand how chemotherapies interact with the immune system, so researchers can get the best synergy between the two.
How Chemotherapy Affects Anti-Tumor Immunity
Chemotherapies can change anti-tumor immunity in several ways.
- Some drugs, such as anthracyclines, trigger immunogenic cell death. This releases danger signals like HMGB1 that activate antigen presenting cells (APCs), which in turn trigger anti-tumor T cell responses.
- Standard apoptosis triggered by many other drugs is often non-immunogenic.
- Chemotherapies can also cause lymphopenia, which cuts both ways for anti-tumor immunity: it can reduce anti-tumor effector T cells, but it can also reduce regulatory T cells and myeloid-derived suppressor cells (MDSC).
Gemcitabine and 5-FU Activate the NLRP3 Inflammasome
In the January issue of Nature Medicine, Bruchard et al. showed that two widely prescribed chemotherapy drugs, gemcitabine and 5-fluorouracil (5-FU), activate the NLRP3 (NOD-like receptor family, pyrin domain containing-3) inflammasome complex in MDSCs. This activation disrupts anti-tumor immunity and reduces how well these drugs work.
The NLRP3 inflammasome activates in response to damage-associated molecular patterns (DAMPs) released during infection with many pathogens. NLRP3 activation forms a multi-protein inflammasome complex that activates caspase-1. IL-1b is a pro-inflammatory cytokine. It starts as an inactive pro-peptide and needs processing by caspase-1 to become active and secreted — making it a major inflammasome effector molecule.
In the Bruchard et al. study, gemcitabine and 5-FU activated the NLRP3 inflammasome complex in MDSCs, which triggered the expected activation of caspase-1 and IL-1b. By contrast, the chemotherapy drugs Deticene, taxol, oxaliplatin, mitomycin C, and doxorubicin did not activate this pathway. The researchers found that cathepsin B, released from damaged lysosomes into the cytosol, triggers NLRP3 activation by gemcitabine and 5-FU. Notably, colorectal cancer patients showed higher serum IL-1b, along with more caspase-1 and cathepsin B activity in circulating MDSCs, one day after 5-FU treatment — confirming these findings in humans.
A Pro-Tumor Role for TH17 Cells
Studies of the subset of CD4+ T helper cells that produce IL-17 (TH17) have found both helpful and harmful roles for these cells in cancer. It’s still unclear what determines which role they play.
In this study, IL-1b released by 5-FU-treated MDSCs drove CD4+ T cells to become TH17 cells. 5-FU treatment also boosted IL-17 production in PBMCs from colorectal cancer patients. Mice lacking inflammasome components or IL-17 survived longer when treated with 5-FU — showing that in mice, 5-FU-induced TH17 cells play a pro-tumor role. Whether 5-FU-induced TH17 cells also promote tumor growth in human patients is still an open question.
Blocking IL-1b Could Boost Chemotherapy
Finally, treating mice with the soluble form of IL-1Ra blocked the effects of IL-1b and boosted the anti-tumor effects of 5-FU. This suggests blocking IL-1b could be a smart immunotherapy strategy for making 5-FU and gemcitabine chemotherapy work better.
In conclusion, this study identified key mechanisms by which gemcitabine and 5-fluorouracil affect the immune system in mouse models and human cancer patients. Chemotherapy drugs damage cells through many different mechanisms. Understanding how each drug interacts with the immune system will be important for building strong synergy between chemotherapy 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).
