A pair of new studies reveals that the composition of the microbiome alters effi cacy of immune checkpoint blockade in mouse cancer models. A pair of new studies reveals that the composition of the microbiome alters effi cacy of immune checkpoint blockade in mouse cancer models. CITATION: Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science 2015; Nov 5. pii: aac4255. CITATION: Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; Nov 5. pii: aad1329. One of the biggest success stories in immunomodulatory therapy is the use of T cell checkpoint blockade in cancer patients. Since the U.S. Food and Drug Administration approved ipilimumab (anti–CTLA-4) in 2011, these checkpoint inhibitors, which now include nivolumab (anti–PD-L1) and pembrolizumab (anti–PD-1), have revolutionized treatment for a number of malignancies. But while these new reagents offer cancer patients more hope than ever before, responses to therapy are highly variable between individuals. In two recent studies, researchers identified an important factor that determines responsiveness to checkpoint blockade in mouse models and thus might underlie some of this variability: the composition of the gut microbiome. Vétizou and colleagues began their investigation with the finding that CTLA-4 blockade was less effective in reducing tumor burden in mice housed under germ-free conditions compared with those housed under specific-pathogen–free conditions. Similarly, Sivan and colleagues noticed that genetically identical mice purchased from two different vendors differed in their responsiveness to anti–PD-L1 antitumor therapy, but that these differences were erased when the animals were cohoused for a period of time prior to initiating the experiment. Both studies identified specific bacterial subspecies that increase responsiveness to antitumor immunotherapy: Vétizou et al showed that oral gavage of Bacteroides fragilis, immunization with B. fragilis polysaccharides or adoptive transfer of B. fragilis-specific T cells into mice that subsequently received a tumor inoculum resulted in increased efficacy of anti–CTLA-4 in controlling tumor growth, while the data of Sivan et al reveal that inoculation with Bifidobacterium organisms resulted in better control of melanoma tumors and increased responsiveness to anti–PD-1 treatment (Figure 1). Mechanistically, both studies ascribed this increased responsiveness to increased dendritic cell activation, including increased expression of transcripts encoding CD40, CD70, intercellular adhesion molecule (ICAM) and class II MHC molecules, as well as secretion of the immunostimulatory cytokine interleukin-12 (IL-12). In the Silvan study, the effect required both live bacteria and an intact CD8+ T cell compartment, suggesting that the salutary effect on tumor burden was mediated indirectly through the enhancement of tumor-specific CD8+ T cell responses. The implications for transplantation are evident and far reaching. The data suggest that the composition of the microbiome could alter the baseline strength of alloreactivity, independently of type or degree of immunosuppression. This supposition warrants investigation in both experimental and clinical settings, and under conditions of differing types of organ and degrees of donor/recipient disparity. For instance, it is possible that the composition of the microbiota could affect immune responses to tissues that directly interface with it (eg, skin, lung) more than those that do not (eg, heart, kidney). The results of these studies highlight an added complexity in the system in that each identified a different bacterial species that promoted the efficacy of a unique immunotherapeutic reagent. These findings raise the intriguing possibility that distinct species within the microbiome (or their absence) might better facilitate the efficacy of one type of immunosuppression over another. Of course, during transplantation our goal is not to stimulate the immune response but rather to quell it, and these studies both identified bacterial species that are implicated in the activation of host dendritic cells and the priming of antitumor responses. Can we identify components of the microbiome that serve to dampen innate immune activation and mollify subsequent adaptive immune responses? Or, as transplanters, will we simply be striving for the absence of these immunostimulatory species in graft recipients? Understanding the answers to these questions will shed light on the therapeutic potential of altering patient microbiota to potentially tip the balance from alloimmunity to tolerance during transplantation.
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Feb 21, 2024
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