CD47 suppresses phagocytosis by repositioning SIRPA and preventing integrin activation

SummaryMacrophages must engulf dead cells, debris, and pathogens, while selecting against healthy cells to prevent autoimmunity. Healthy cells express CD47 on their surface, which activates the SIRPA receptor on macrophages to suppress engulfment. Cancer cells overexpress CD47 to evade clearance by the innate immune system, making the CD47-SIRPA signaling axis an appealing therapeutic target. However, the mechanism by which CD47-SIRPA inhibits engulfment remains poorly understood. Here, we dissect SIRPA signaling using a reconstituted target with varying concentrations of activating and inhibitor ligands. We find that SIRPA is excluded from the phagocytic synapse between the macrophage and its target unless CD47 is present. Artificially directing SIRPA to the kinase-rich synapse in the absence of CD47 activates SIRPA and suppresses engulfment, indicating that the localization of the receptor is critical for inhibitory signaling. CD47-SIRPA inhibits integrin activation in the macrophage, reducing macrophage-target contact and suppressing phagocytosis. Chemical activation of integrins can override this effect and drive engulfment of CD47-positive targets, including cancer cells. These results suggest new strategies for overcoming CD47-SIRPA inhibition of phagocytosis with potential applications in cancer immunotherapy.

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Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response

Cancers ◽

10.3390/cancers12123827 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3827

Author(s):

Richard Baugh ◽

Hena Khalique ◽

Leonard W. Seymour

Keyword(s):

Immune System ◽

Immune Responses ◽

Cancer Cells ◽

Innate Immune System ◽

Cell Transformation ◽

Innate Immune ◽

Immune Mediated ◽

Pathogenic Viruses ◽

Group 2 ◽

Immune Defences

The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8+ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, expression is significantly increased in response to various types of cellular stress, viral infection, and tumour cell transformation. In order to evade immune-mediated cytotoxicity, both pathogenic viruses and cancer cells have evolved various mechanisms of subverting immune defences and preventing NKG2DL expression. Comparisons of the mechanisms employed following virus infection or malignant transformation reveal a pattern of converging evolution at many of the key regulatory steps involved in NKG2DL expression and subsequent immune responses. Exploring ways to target these shared steps in virus- and cancer-mediated immune evasion may provide new mechanistic insights and therapeutic opportunities, for example, using oncolytic virotherapy to re-engage the innate immune system towards cancer cells.

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The Role of the Innate Immune System in Cancer Dormancy and Relapse

Cancers ◽

10.3390/cancers13225621 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5621

Author(s):

Noah M. Chernosky ◽

Ilaria Tamagno

Keyword(s):

Immune System ◽

Cancer Cells ◽

Cancer Progression ◽

Immune Cells ◽

Innate Immune System ◽

Immune Escape ◽

Disease Process ◽

Innate Immune ◽

Cancer Dormancy

Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers.

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Elucidating tumor immunosurveillance and immunoediting: a comprehensive review

Ciência Animal Brasileira ◽

10.1590/1809-6891v22e-68544 ◽

2021 ◽

Vol 22 ◽

Author(s):

Estela Vieira de Souza Silva ◽

Eduardo de Paula Nascente ◽

Marina Pacheco Miguel ◽

Carlos Eduardo Fonseca Alves ◽

Veridiana Maria Brianezi Dignani de Moura

Keyword(s):

Immune System ◽

Innate Immune System ◽

Tumor Antigens ◽

Selective Pressure ◽

Innate Immune ◽

Tumor Immunosurveillance ◽

Neoplastic Process ◽

Prevention And Cure ◽

Antigenic Profile ◽

New Strategies

Abstract The action of the immune system against neoplastic diseases has become one of the main sources of research. The biological pathways of this system are known to contribute in limiting the progression and elimination of the tumor, and are delineated by concepts and mechanisms of immunosurveillance and immunoediting. Immunosurveillance is considered the process by which the immune system recognizes and inhibits the neoplastic process. The concept of immunoediting arises in the sense that immune system is able to shape the antigenic profile of the tumor due to selective pressure, based on the stages of tumor elimination, balance and evasion. The immune response occurs against tumor antigens and changes in the tumor microenvironment, involving different components of the innate immune system, such as T cells, natural Killer cells, B lymphocytes and macrophages. In this sense, knowing these concepts and understanding their respective mechanisms becomes essential in the investigation of new strategies for cancer prevention and cure. Thus, this review presents historical aspects and definitions of immunosurveillance and tumor immunoediting, with emphasis on its importance and applicability, such as on the different methods used in immunotherapy.

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