Dr. Cuiffo Presents at AACR

Biomodels attends and presents at the Annual American Association for Cancer Research Conference, April 1-5, 2017.

Meeting location: Walter E. Washington Convention Center, Washington, DC.

Dr. Benamin G. Cuiffo will present “The Gastrointestinal Microbiome and its Composition are Critical for Anti-tumor Efficacy of Immune Checkpoint Inhibition by αPD-L1.” Please see abstract below.

Background: The intestinal microbiome has become increasingly appreciated as a significant mediator of systemic antitumor immunity/response in both naïve and treatment contexts.  In naïve contexts, an intact intestinal microbiome has been demonstrated to enhance tumorigenesis, and its composition reported to mediate primary tumor growth kinetics.  In the context of cancer treatment, antibiotic depletion of the intestinal microbiota has been reported to inhibit the efficacy of cyclophosphamide and that of the immune checkpoint inhibitor anti-CTLA4, and compositional modulation of the intestinal microbiota has been reported as sufficient to enhance the antitumor efficacy of anti-PD-L1.

Methods: Here, we assessed the impact of the presence and composition of commensal microbiota on in vivo tumor growth kinetics of B16.F10.SIY melanoma in specific pathogen free (SPF) or in germ-free (GF) C57BL/6 mice.  We asked if compositional differences of commensal microbiota influenced the antitumor efficacy of αPD-L1 mAb checkpoint inhibition by comparing in vivo tumor growth kinetics of B16.F10.SIY melanoma in C57BL/6 mice sourced from different vendors (Jackson (JAX)/Taconic (TAC)), handed under SPF protocols and under identical treatment regimens. Finally, we probed for mechanistic insights underlying our observations by performing flow cytometric immunophenotyping of tumor-infiltrating lymphocyte (TIL) populations, correlating with tumor growth and IFNγ induction.

Results: B16.F10.SIY tumor growth was significantly inhibited in germ-free mice compared to SPF mice.  Germ-free mice did not respond to αPD-L1 mAb treatment, while SPF mice responded, though cumulative differences did not reach statistical significance.  Furthermore, compositional differences of microbiome appeared to impact antitumor response to αPD-L1 mAb treatment.  On average, tumors of TAC C57BL/6 mice handled under SPF protocols appeared to respond to αPD-L1 mAb treatment, while genetically similar SPF JAX mice did not respond; however, cumulative differences did not reach statistical significance.  Immunotyping of TILs provided mechanistic insights, and suggested that tumors of GF mice carried increased populations of CD3+ T-cells compared to tumors of SPF mice.  Additionally, while CD8+ cytotoxic T-cell TIL populations were comparable in isotype control mAb treated SPF animals, αPD-L1 mAb treatment increased mean %CD8+ of CD3+EpCam- TIL population only in TAC SPF mice; identical treatment appeared to decrease CD8+ T-cell populations in TAC GF mice and JAX SPF mice.

Conclusions: These observations suggest that the presence and composition of commensal microbiota may exert significant influence on tumor growth kinetics and potential of response to immunomodulatory anticancer therapies, including immune checkpoint inhibition via αPD-L1 mAb. Rational modulation of the microbiome might therefore be utilized to enhance response to current and emerging immunomodulatory anticancer treatment strategies.

To receive a PDF copy of the poster please email info@biomodels.com.