Dissertation/Thesis Abstract

Modulation of Integrin CD11b/CD18 as a Novel Therapeutic Strategy against Lung Cancer
by Geraghty, Terese, Ph.D., Rush University, 2019, 78; 27544646
Abstract (Summary)

Globally, cancer is among the leading causes of death with 1 in 6 deaths due to cancer. Lung cancer is leading cause of cancer-related death accounting for more deaths than breast, prostate, and colon cancer combined. Current treatment options for lung cancer patients vary by stage and type of disease, but include surgical resection whenever possible, chemotherapy and radiotherapy when applicable. These treatments help control disease progression, but lack specificity and have unwanted side effects. Retraining the immune system to respond to cancer is an attractive alternative to chemo- or radio- therapies because it has the ability to circumvent some of these severe side effects. For example, immune checkpoint inhibitors (e.g., anti-PD1, anti-CTLA-4, etc.), work by augmenting the anti-tumor T cell response, and have had a significant impact on improving the survival of lung cancer patients. Although, these new therapies have done well to improve lung cancer patient survival, there is still more room for development of targeted therapeutics that improve patient outcomes.

Beyond T cell targeted immunotherapy, there are increasing efforts to find other immune cells as targets for new immunotherapies. Lung tumors have large numbers of tumor associated macrophages (TAMs) which suppress the adaptive immune response, increase neo-vascularization of the tumor, and secrete pro-tumor factors to promote tumor growth. Integrin CD11b/CD18 (also known as Mac-1, CR3 and αMβ2) is highly expressed on myeloid cells, including TAMs, and plays an important role in innate cell recruitment and other biological functions. GB1275 (previously known as ADH-503) is a novel small molecule CD11b allosteric modulator. GB1275 is currently in Phase 1/2 clinical development for various cancer types. Here, we describe our pre-clinical studies to investigate the impact of CD11b modulation in the context of lung cancer.

To assess the role of CD11b in regulating lung tumor growth, we studied lung tumor growth in the absence of CD11b using CD11b knockout (KO) mice, by pharmacologically modulating CD11b in WT mice by treatment with GB1275, or in the context of genetically modulated CD11b using CD11b knock-in (KI) mice. All tumors were propagated in the Lewis lung carcinoma (LLC) syngeneic tumor model. LLC tumors grew faster and had heavier tumor burden in CD11b KO mice as compared to WT controls. In contrast to CD11b KO mice, pharmacologic modulation of CD11b by GB1275 treatment significantly reduced tumor growth. We developed a transgenic CD11b knock-in (KI) mouse that renders CD11b in a partially active state by introducing a point mutation at residue 332 of the ligand binding CD11b A/I-domain, changing isoleucine to glycine (I332G). CD11b KI mice showed a significant reduction in both the size and the rate of LLC tumor growth, as compared to the WT mice, mimicking treatment effects with GB1275. Tumor immune profiling showed a significant reduction in monocyte, granulocyte, and mature TAM infiltration in GB1275-treated and CD11b KI tumors. Dendritic cell populations changed to enhance antigen cross presentation as a result of CD11b modulation. There was an increase in the frequency of CD8+ cytotoxic T lymphocytes and decrease of FoxP3+ regulatory T cells in GB1275-treated and CD11b KI tumors. CD11b modulation affected TAM polarization manifested by increased frequencies of M1-like F4/80+MHCII+ TAMs and decreased M2-like F4/80+CD206+ TAMs and from gene expression profiling of CD11b-modulated macrophages. CD11b-modulated macrophages showed significant downregulation of Ccl2 mRNA levels, which resulted in less CCL2 protein secreted into circulation. Taken together, these results indicate that CD11b modulation not only reprograms TAMs to enhance the T cell response, but also works by reducing trafficking of new TAMs in the lung tumor microenvironment to reduce the overall inflammatory burden.

Overall, CD11b modulation affects both monocyte/macrophage recruitment to lung tumors and reprograms TAMs to enhance the anti-tumor immune response. There are many antagonism approaches to inhibit pro-tumoral TAMs, but here we describe an agonistic approach via CD11b modulation. As CD11b+ cells are highly abundant in human lung tumors, targeting CD11b via allosteric modulation is a novel therapeutic strategy against lung cancer.

Indexing (document details)
Advisor: Gupta, Vineet
Commitee: Shafikhani, Sasha, Maki, Carl, Dudek, Arek, Landay, Alan
School: Rush University
Department: Immunology / microbiology
School Location: United States -- Illinois
Source: DAI-B 81/7(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Immunology, Oncology, Cellular biology
Keywords: CD11b, Immunotherapy, Integrin, Lung cancer, Macrophages
Publication Number: 27544646
ISBN: 9781392514290
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