Integrin CD11b activation drives anti-tumor innate immunity

Schmid, Michael C.; Khan, Samia Q.; Kaneda, Megan M.; Pathria, Paulina; Shepard, Ryan; Louis, Tiani L.; Anand, Sudarshan; Woo, Gyunghwi; Leem, Chris; Faridi, Mohd Hafeez; Geraghty, Terese; Rajagopalan, Anugraha; Gupta, Seema; Ahmed, Mansoor; Vázquez-Padrón, Roberto I.; Cheresh, David A.; Gupta, Vineet; Varner, Judith A.

doi:10.1038/s41467-018-07387-4

Cited by 236 publications

(202 citation statements)

References 50 publications

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“…Next, we evaluated the sensitivity of different macrophage phenotypes to MEKi in vitro and found that both 2 and 3 days of MEKi treatment significantly augmented apoptosis of M2-like macrophages ( Figure 5D ). Reprogramming rather than depletion of macrophages has been recently suggested as a successful strategy to increase sensitivity towards immunoncology (33,34). Therefore, we also sought to assess if MEKi was able to induce reprogramming of macrophages towards anti-tumor (pro-inflammatory) phenotypes.…”

Section: Resultsmentioning

confidence: 99%

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

Filippini

Neander

Delfino

et al. 2019

Preprint

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2The RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many 3 compounds have been developed and tested for the treatment of KRAS-driven cancers, including 4 pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced 5 by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We 6 evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a 7 multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of 8 MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that 9 transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA 10 subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse 11 PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses 12 showed that MEKi reshapes the immune landscape of PDA by depleting rather than 13 reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of 14 macrophages is observed early in the course of in vivo treatment and is at least partially due to 15 their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to 16 interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior 17 antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than 18 simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic 19 remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, 20 which substantially improves the antitumor activity of gemcitabine. 22Pancreatic ductal adenocarcinoma (PDA) has the lowest survival rate of all cancers (1). 25Current therapeutic strategies are mostly based on combination of chemotherapeutic agents, 26 which provides intermittent response and modest survival benefit in the advanced disease setting 27 (2,3). Results from recent clinical trials showed that immune-checkpoint based therapy is rarely 28 active in PDA (4). The complex and heterogenous PDA microenvironment is reported to play a 29 major role in mediating resistance to both chemotherapy and immune therapy (5). In human PDA 30 stromal non-malignant cells often outnumber neoplastic cells, with fibroblasts and macrophages 31 being the dominants cellular components (6). 32Activating mutations of the GTPase KRAS are a nearly universal feature of PDA (7). Activated 33 KRAS engages a multitude of pathways, including the RAF/MEK/ERK (MAP Kinase) pathway, 34 which regulates cellular processes such as proliferation and cell survival (8). Preclinical mouse 35 models show that the oncogenic KRAS-induced cytokine milieu likely contributes to the highly 36 immunosuppressive microenvironment observed already at the preneoplastic PanIN stage (9). In 37 addition to non-cell autonomous effects, KRAS activation and increased activity through the MAP 38Kinase pathway induce cell-intrinsic u...

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Section: Resultsmentioning

confidence: 99%

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

Filippini

Neander

Delfino

et al. 2019

Preprint

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“…[33][34][35] Furthermore, a former study showed that pharmacological activation of CD11b/ CD18 could promote pro-inflammatory macrophage polarization and suppress tumor growth in animal models of murine and human cancer. 36 CR3 and CR4 were proved to enable complement-dependent cell cytotoxicity toward antibody-coated tumor cells as part of biological therapy. 37 As revealed in our sub-network, KEGG pathways were also predicted correlations with the hematopoietic cell lineage and immunodeficiency, providing a clue that ITGAM, ITGB2 and ITGAX might also be involved in AL amyloidosis progression via regulating immune response.…”

Section: Discussionmentioning

confidence: 99%

<p>Identification of Candidate Genes and Therapeutic Agents for Light Chain Amyloidosis Based on Bioinformatics Approach</p>

Bai¹,

Hong-hua²,

Bai

2020

PGPM

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Systemic amyloid light chain (AL) amyloidosis is a rare plasma cell disease. However, the regulatory mechanisms of AL amyloidosis have not been thoroughly uncovered, identification of candidate genes and therapeutic agents for this disease is crucial to provide novel insights into exploring the regulatory mechanisms underlying AL amyloidosis. Methods: The gene expression profile of GSE73040, including 9 specimens from AL amyloidosis patients and 5 specimens from normal control, was downloaded from GEO datasets. Differentially expressed genes (DEGs) were sorted with regard to AL amyloidosis versus normal control group using Limma package. The gene enrichment analyses including GO and KEGG pathway were performed using DAVID website subsequently. Furthermore, the protein-protein interaction (PPI) network for DEGs was constructed by Cytoscape software and STRING database. DEGs were mapped to the connectivity map datasets to identify potential molecular agents of AL amyloidosis. Results: A total of 1464 DEGs (727 up-regulated, 737 down-regulated) were identified in AL amyloidosis samples versus control samples, these dysregulated genes were associated with the dysfunction of ribosome biogenesis and immune response. PPI network and module analysis uncovered that several crucial genes were defined as candidate genes, including ITGAM, ITGB2, ITGAX, IMP3 and FBL. More importantly, we identified the small molecular agents (AT-9283, Ritonavir and PKC beta-inhibitor) as the potential drugs for AL amyloidosis. Conclusion: Using bioinformatics approach, we have identified candidate genes and pathways in AL amyloidosis, which can extend our understanding of the cause and molecular mechanisms, and these crucial genes and pathways could act as biomarkers and therapeutic targets for AL amyloidosis.

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“…This highlights the therapeutic relevance of PG2 as a potential CSC-targeting pharmacological agent and putative component of an effective anticancer therapeutic strategy for patients with NSCLC. TAMs/MDMs display of an anti-cancer phenotype and association with reduced angiogenesis, reversed immune suppression, acquisition of a benign phenotype, repressed invasiveness, and invariably disease remission (Davies et al, 2013;Hagemann et al, 2009;Schmid et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…To gain some mechanistic insight into the observed PG2 pharmacological activities, we examined its effect on cancer-complicit component of the inflammatory cascade the nuclear factor kappa protein, beta subunit (NF-B) (Shigdar et al, 2014), pro-angiogenic marker CD31 and pro-inflammatory macrophage marker CD11b (Schmid et al, 2018). Using tumor samples obtained from the mice, we demonstrated that treatment with 0.5 mg/kg/day cisplatin alone, 3 mg/kg/day PG2 alone, or PG2/cisplatin combination down-regulated the expression of NF-B, and CD31proteins mildly, moderately and strongly, respectively, while up-regulating CD11b protein expression level in increasing order of magnitude (Fig.…”

Section: Pg2 Suppresses Tumorigenicity and Metastasis In Syngeneic C5mentioning

confidence: 99%

Astragalus Polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer

Bamodu¹,

Kuo²,

Wang³

et al. 2019

Preprint

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Background: Recently we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improve quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade, against the background that inflammatory cells including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. Purpose: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade, enhance anticancer immunity, and the therapeutic implication of same in patients with lung cancer. Methods and Results: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro, positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that mice treated with PG2 exhibited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibition of xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscresia and weight-loss was markedly suppressed. Conclusion: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation, and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin; thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.

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Integrin CD11b activation drives anti-tumor innate immunity

Cited by 236 publications

References 50 publications

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

<p>Identification of Candidate Genes and Therapeutic Agents for Light Chain Amyloidosis Based on Bioinformatics Approach</p>

Astragalus Polysaccharides (PG2) Enhances the M1 Polarization of Macrophages, Functional Maturation of Dendritic Cells, and T Cell-Mediated Anticancer Immune Responses in Patients with Lung Cancer

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