A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade
Menée à l'aide de deux xénogreffes orthotopiques de cancer mammaire métastatique sur un même modèle murin, cette étude identifie des programmes transcriptionnels associés à la réponse tumorale à un traitement par inhibiteur de point de contrôle immunitaire
Immune checkpoint blockade (ICB) has revolutionized treatment of many cancer types, but the majority of treated patients still do not respond to ICB. There is an urgent need to identify predictive biomarkers of response prior to or shortly after therapy initiation, as well as the underlying mechanisms. Here we utilize a model of bilateral tumor implantations followed by resection and immunotherapy-response assessment to study the tumor microenvironment shortly following treatment, identifying biomarkers for response or resistance at early time points. Our biomarker gene signatures derived from CD8+ T cells significantly segregate patients by survival and associate with patient response to ICB. Our findings provide a general approach for studying mechanisms of resistance to ICB and discovering predictive biomarkers of response.Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3−/− mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.All study data are included in the article and SI Appendix.
Proceedings of the National Academy of Sciences , résumé, 2019