13th September, 2019. Dr Chee L Khoo
Checkpoint molecules are key regulators of the immune system. These checkpoint molecules are expressed by T cells and are essential for maintenance of immunological tolerance by preventing the unimpeded activation of T cells. Tumour cells capitalise on these checkpoint molecules to protect themselves from attacks by the immune system. Checkpoint therapy block inhibitory checkpoints, restoring immune system function. A significant proportion of patients do not experience objective responses, and when responses do occur, may not be durable. Further, while immune checkpoint inhibitors (ICI) have been a qualified success in the treatment of various malignancies, a significant proportion of patients continue to experience treatment-limiting toxicity. We look at some of those adverse effects in June 2019.
There is also mounting evidence to support the role of the gut microbiome in shaping systemic ICI responses and modulation of immune related adverse events (1). Within a human organism, there are trillions of microbes as numerous as human cells, that interact with the host constantly at numerous sites (including the skin and mucosal surfaces such as the gastrointestinal tract) throughout development. They play such large role in numerous host functions including immunity (2-3).
The crosstalk between microbiota and the immune system at the level of the gut is extensive and critical, and not only allows for the tolerance of commensal bacteria and oral food antigens, but also enables the immune system to recognize and attack opportunistic bacteria thereby preventing bacterial invasion and infection.
Germ-free mice that lack intestinal microbiota are noted to have severe defects in immunity, with an absent mucous layer, altered IgA secretion and reduced size and functionality of Peyer’s patches and draining mesenteric lymph nodes (4-5). Disruption of the delicate balance of commensal bacteria is seen in the setting of dysbiosis, which is characterised by a less diverse and less stable microbiota, with potential enrichment of opportunistic pathogenic bacteria (6). Dysbiosis can lead to impaired local, loco-regional, and systemic immune responses with breakdown of mucosal barriers.
One of the earliest demonstrations of the role of the gut microbiota in response and toxicity to cancer therapy was in the setting of allogeneic stem cell transplant (allo-HSCT) for hematologic malignancies. Dysbiosis in the setting of HSCT has also been associated with differences in long-term survival, with patients having a lower diversity of microbiota in their gut at the time of HSCT having shortened overall survival and higher mortality rates (specifically transplant-related mortality) compared to those with a high diversity of gut microbiota (7).
The impact of the gut microbiota on response to immune checkpoint blockade was first studied in mouse models, with landmark publications in Science in 2015 demonstrating that the composition of the gut microbiota could influence the response to immune checkpoint inhibitors (8-9). Modulation of the gut microbiota may represent a novel and important adjunct to current anti-cancer therapeutic modalities. However, several ongoing and planned clinical trials involving dietary intervention, designer probiotics and faecal microbiota transplant will investigate the therapeutic potential of manipulation of the gut microbiota directly in cancer patients. It is not yet clear what composition of the gut microbiome is optimal to facilitate anti-tumour immune responses and a diverse range of therapeutic options exist to change the microbiome that need to be tested carefully in the context of clinical trials.
To complicate matters further, does the timing of broad-spectrum antibiotic treatment alter responsive to ICIs in anti-cancer therapy? Exposure to broad-spectrum antibiotic therapy may adversely influence outcomes of ICI therapy (10) through modulation of intestinal microbiota,(11). In a recent novel study, broad spectrum antibiotics up to 30 days prior to commencement of ICI was associated with worse treatment outcomes and overall survival compared with broad spectrum antibiotics initiated concurrently with ICI (12).
We have a lot of work to do to understand the interaction between ICI, microbiome and many other factors including broad spectrum antibiotics.
- Gopalakrishnan V., Helmink B.A., Spencer C.N., Reuben A., Wargo J.A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33(4):570–580.
- SENDER R, FUCHS S & MILO R 2016 Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLOS Biology, 14, e1002533. [PubMed: 27541692]
- MORGAN XC & HUTTENHOWER C 2012 Chapter 12: Human microbiome analysis. PLoS Comput Biol, 8, e1002808. [PubMed: 23300406]
- JOHANSSON ME, JAKOBSSON HE, HOLMEN-LARSSON J, SCHUTTE A, ERMUND A, RODRIGUEZ-PINEIRO AM, ARIKE L, WISING C, SVENSSON F, BACKHED F & HANSSON GC 2015 Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization. Cell Host Microbe, 18, 582–92. [PubMed: 26526499]
- SPILJAR M, MERKLER D & TRAJKOVSKI M 2017 The Immune System Bridges the Gut Microbiota with Systemic Energy Homeostasis: Focus on TLRs, Mucosal Barrier, and SCFAs. Front Immunol, 8, 1353. [PubMed: 29163467]
- FROSALI S, PAGLIARI D, GAMBASSI G, LANDOLFI R, PANDOLFI F & CIANCI R 2015 How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology. J Immunol Res, 2015, 489821. [PubMed: 26090491]
- TAUR Y, JENQ RR, PERALES MA, LITTMANN ER, MORJARIA S, LING L, NO D, GOBOURNE A, VIALE A, DAHI PB, PONCE DM, BARKER JN, GIRALT S, VAN DEN BRINK M & PAMER EG 2014 The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood, 124, 1174–82. [PubMed: 24939656]
- VETIZOU M, PITT JM, DAILLERE R, LEPAGE P, WALDSCHMITT N, FLAMENT C, RUSAKIEWICZ S, ROUTY B, ROBERTI MP, DUONG CP, POIRIER-COLAME V, ROUX A, BECHAREF S, FORMENTI S, GOLDEN E, CORDING S, EBERL G, SCHLITZER A, GINHOUX F, MANI S, YAMAZAKI T, JACQUELOT N, ENOT DP, BERARD M, NIGOU J, OPOLON P, EGGERMONT A, WOERTHER PL, CHACHATY E, CHAPUT N, ROBERT C, MATEUS C, KROEMER G, RAOULT D, BONECA IG, CARBONNEL F, CHAMAILLARD M & ZITVOGEL L 2015 Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 350, 1079–84. [PubMed: 26541610]
- SIVAN A, CORRALES L, HUBERT N, WILLIAMS JB, AQUINO-MICHAELS K, EARLEY ZM, BENYAMIN FW, LEI YM, JABRI B, ALEGRE ML, CHANG EB & GAJEWSKI TF 2015 Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 350, 1084–9. [PubMed: 26541606]
- Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29(6):1437-1444.
- Weber D, Hiergeist A,Weber M, et al. Detrimental effect of broad-spectrum antibiotics on intestinal microbiome diversity in patients after allogeneic stem cell transplantation: lack of commensal sparing antibiotics. Clin Infect Dis. 2019;
- Pinato, DJ, Howlett S, Ottaviani D., et al. Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. JAMA Oncol. doi:10.1001/jamaoncol.2019.2785