Harnessing the Microbiome to Optimize Response to Immunotherapy

Marina Barcena-Varela, PhD

Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy that is highly aggressive in nature and lacks highly effective therapeutic options. Immune checkpoint inhibitors (ICIs) and other therapeutic strategies targeting the tumor microenvironment have significantly impacted the treatment landscape for CCA; however, outcomes remain poor. The CCA immune microenvironment can be considered “hot” or “cold,” with “hot” tumors being the most likely to respond to ICI therapy.¹ Many trials have been completed or are ongoing that seek to improve ICI response rates in patients with CCA; these have investigated combination ICI therapy with chemotherapy, dual immune therapy, and ICI and targeted therapy combinations.² The gut microbiome is a potential modulator of antitumor immunity and response to ICI therapy, and Marina Barcena-Varela, PhD, and her team hypothesized that “changes in microbiota composition affect CCA tumorigenesis, progression, and response to therapy, and these effects might be exploited to improve response to immunotherapy.”¹

Dr Barcena-Varela described a study she undertook with her colleagues to understand how the microbiome affects CCA tumorigenesis depending on genetic alterations and response to targeted and immunotherapy.¹ They used precision mouse models with various genetic alterations seen in human CCA. NICD;AKT and YAP;AKT tumors were representative of intrahepatic CCA (iCCA) “cold” tumors, and MYC;NICD tumors represented mixed hepatocellular carcinoma (HCC)-iCCA “cold” tumors. The microbiome was manipulated using antibiotic treatments targeting specific subpopulations of the microbiome. Overall, it was found that vancomycin and neomycin treatments did not alter the median survival of NICD;AKT iCCA mouse models; however, antibiotic treatment significantly reduced the median survival of YAP;AKT iCCA mouse models and increased the median survival of MYC;NICD HCC-iCCA mouse models. In general, the growth of NICD;AKT tumors was not affected by antibiotic treatment, YAP;AKT tumors developed faster when mice were treated with antibiotics, and MYC;NICD tumors developed slower when mice were treated with neomycin and vancomycin.¹

The researchers demonstrated that altering the microbiome composition using antibiotics can significantly affect tumor development in certain mouse models with CCA, and the effects are determined by the genetic background of the tumor to determine whether microbiome manipulation is pro-tumorigenic or anti-tumorigenic.¹ Future efforts will aim to identify bacteria populations responsible for observed phenotypes, address how microbiome manipulation can be synergistic with immunotherapy to improve response rates in patients, and understand how genetics play a role in sensitivities to microbiome changes for a personalized approach to CCA management.

Sources:

1. Barcena-Varela M. Harnessing the microbiome for precision cholangiocarcinoma (CCA) immunotherapy. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
2. Xinjun L, Green BL, Xie C, et al. Preclinical and clinical studies of immunotherapy for the treatment of cholangiocarcinoma. JHEP Reports. 2023;5:100723.