Targeting macrophages for enhancing CD47 blockade–elicited lymphoma clearance and overcoming tumor-induced immunosuppression

Abstract

Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. While several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage Non-Hodgkin's Lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47, due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of FDA-approved anti-cancer small molecule compounds, we identified paclitaxel as a potentiator that promotes the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward cancer cells. A combination with paclitaxel dramatically enhanced the anti-cancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases (SFK) signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that is only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment, by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the anti-tumor activities of macrophages.

Low absolute CD4+ T cell counts in peripheral blood: an independent predictor of inferior survival in natural killer/T-cell lymphoma—a retrospective cohort study

“…The immune system often plays an important role in the development and progression of lymphoma. In epidemiologic studies, immune suppression is regarded as a risk factor for NHL ( 22 , 23 ). It is not yet known whether there is a correlation between lymphocytopenia and poor survival and an association between the specific subset of lymphocytes and inferior prognosis.…”

Targeting macrophages in hematological malignancies: recent advances and future directions

“…Blocking the CD47/SIRPα cross talk has been shown to enhance anti-tumor activities. Therefore, blocking the CD47/SIRPα cross talk may be a promising approach for cancer immunotherapy either on its own or via integration with other tumortargeted therapies, as reported in numerous preclinical studies [35,[37][38][39][40]. Clinical studies confirm the importance of inhibiting the CD47/SIRPα interaction in various hematological malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) [41], and relapsed/refractory non-Hodgkin's lymphoma (R/R-NHL) [42].…”

Pro-phagocytic function and structural basis of GPR84 signaling

“…The phagocytic ability of macrophages toward live cancer cells was evaluated by a luminescencebased long-term phagocytosis assay as we previously described 70 . Specifically, luciferaseexpressing Raji cells were co-cultured with bone marrow-derived macrophages (BMDMs) for 24 h in the absence or presence of CD47 blocking antibody (clone B6H12).…”