Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy
Menée à l'aide d'un modèle murin de leucémie, cette étude met en évidence des mécanismes par lesquels un traitement à faible dose de cyclophosphamide sensibilise à une thérapie à base d'anticorps le micro-environnement des cellules tumorales dans la moelle osseuse
Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNF
α from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.
"Low-dose chemotherapy sensitizes persisting tumor microenvironments to antibody therapy "Chemotherapy promotes an acute cytokine response that boosts innate immune activity "Tumor elimination depends on the timing of codosing chemo- and immunotherapy Tumor cells that become treatment resistant by virtue of their bone marrow microenvironment can be targeted by low-dose chemotherapy, which in combination with antibody therapy promotes the ability of the innate immune system to seek out and eradicate these tumor cells.