XBP1 regulates the protumoral function of tumor-associated macrophages in human colorectal cancer.

Macrophages are among the most abundant immune cells in colorectal cancer (CRC). Re-educating tumor-associated macrophages (TAMs) to switch from protumoral to anti-tumoral activity is an attractive treatment strategy that warrants further investigation. However, little is known about the key pathway that is activated in TAMs. In this study, infitrating CD206+ TAMs in CRC were sorted and subjected to RNA-seq analysis. Differentially expressed genes were found to be enriched in unfolded protein response/endoplasmic reticulum stress response processes, and XBP1 splicing/activation was specifically observed in TAMs. XBP1 activation in TAMs promoted the growth and metastasis of CRC. Ablation of XBP1 inhibited the expression of the pro-tumor cytokine signature of TAMs, including IL-6, VEGFA, and IL-4. Simultaneously, XBP1 depletion could directly inhibit the expression of SIRPα and THBS1, thereby blocking "don't eat me" recognition signals and enhancing phagocytosis. Therapeutic XBP1 gene editing using AAV2-sgXBP1 enhanced the anti-tumor activity. Together, XBP1 activation in TAMs drives CRC progression by elevating pro-tumor cytokine expression and secretion, as well as inhibiting macrophage phagocytosis. Targeting XBP1 signaling in TAMs may be a potential strategy for CRC therapy.

Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy.

Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.

Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy.

Cancer immunotherapy has revolutionized the paradigm for the clinical management of cancer. While FDA-approved cancer immunotherapies thus far mainly exploit the adaptive immunity for therapeutic efficacy, there is a growing appreciation for the importance of innate immunity in tumor cell surveillance and eradication. The past decade has witnessed macrophages being thrust into the spotlight as critical effectors of an innate anti-tumor response. Promising evidence from preclinical and clinical studies have established targeting macrophage phagocytosis as an effective therapeutic strategy, either alone or in combination with other therapeutic moieties. Here, we review the recent translational advances in harnessing macrophage phagocytosis as a pivotal therapeutic effort in cancer treatment. In addition, this review emphasizes phagocytosis checkpoint blockade and the use of nanoparticles as effective strategies to potentiate macrophages for phagocytosis. We also highlight chimeric antigen receptor macrophages as a next-generation therapeutic modality linking the closely intertwined innate and adaptive immunity to induce efficacious anti-tumor immune responses.

TRIM59 suppresses NO production by promoting the binding of PIAS1 and STAT1 in macrophages.

Macrophages, which can secret various inflammation mediators, have an essential role in tumor growth and metastasis. However, the mechanism(s) to regulate the production of inflammation mediator is not completely clear. Here we found that TRIM 59 could inhibit the production of NO and the expression of inducible nitric oxide synthase (iNOS), cytochrome c oxidase subunit2 (COX2) and TNFα. TRIM59 mediated suppression on nitric oxide (NO) production is through inhibiting the activation of JAK2-STAT1 signal pathway. In response to LPS, TRIM59 in macrophages was translocated from cytoplasm to nucleus and directly bound with STAT1. During this process, TRIM59 could recruit much more PIAS1 to bind with STAT1 to suppress the activation of STAT1. Finally, TRIM59 modified macrophages could promote tumor growth. Thus, TRIM59 mediated suppression on NO production by promoting the binding of PIAS1 and STAT1 in macrophages may regulate tumor growth.

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.

Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.