Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy

Abstract

Therapy-resistant microenvironments represent a major barrier towards 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 TNFα 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 chemo-immunotherapeutic regimen represents a potent strategy for using conventional anti-cancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…Furthermore, M2-skewed macrophages showed increased in vitro phagocytic capacity of rituximab-opsonized chronic lymphocytic leukemia cells in contrast with M1 macrophages, suggesting that CD163 is a rational marker to identify TAM that participate in rituximab-mediated antitumor responses. 85 However, it is notable that the recent study by Pallasch et al 86 reported that antitumor responses to an anti-CD20 antibody were achieved in the macrophage-rich environment in the spleen, but not in the macrophage-poor bone marrow. Fig.…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…103 Preclinical and translational advances. Within the abundant preclinical literature that has been published during the last 13 months on ICD-inducing chemotherapeutics, we found of particular interest the works of: (1) Pallasch and colleagues (Massachusetts Institute of Technology; Cambridge, MA, US), who demonstrated that cyclophosphamide induces an acute secretory phenotype in malignant cells, stimulating the release of various immunostimulatory cytokines that promotes a macrophagedriven, tumor-targeting innate immune response; [104][105][106] (2) Tavora and collaborators (Barts Cancer Institute; London, UK), who showed that the inhibition of protein tyrosine kinase 2 (PTK2, also known as FAK) [107][108][109] in the endothelial tumor [130][131][132][133] in the establishment of a collagenenriched tumor microenvironment contributing to the resistance of (at least a subset of) breast carcinomas to doxorubicin. 134 Recently initiated clinical trials.…”

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…Combination therapy of cyclophosphamide with the antibody eliminated residual disease by inducing a secretion phenotype that increased infiltration of macrophages into the bone marrow and enhanced phagocytic activity (Pallasch et al, 2014).…”