Potential mechanism of radiotherapy combined with CD47 blockade against tumor

In preclinical models of SCLC, CD47 blockade was found to be effective in enhancing the local antitumor effects of radiotherapy. "Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect," a related study, was published in Nature Cancer. According to the findings, systemic activation of antitumor macrophages following radiation therapy and CD47 blockade may be especially important for patients with metastatic disease.

In recent years, there has been a surge in interest in combining radiotherapy and immunotherapy, with the most common strategy being to promote systemic T cell activation. In this context, the release of tumor antigens from irradiated cancer cells that are dead or dying is thought to be a mechanism that could boost the initiation of antigen-specific T cells, thereby activating an adaptive immune response against any remaining cancer cells. This concept has resulted in the start of a large number of clinical trials. Radiotherapy, on the other hand, can activate both innate and adaptive immune responses that can be pro- or anti-tumor growth. As a result, it is critical to continue researching combination therapies that include immune cell types other than T cells.

Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and kills over 200,000 people globally each year. Patients with SCLC who have localized disease have been treated with first-line radiation therapy combined with chemotherapy for decades. Initially, these patients usually respond well, but then most rapidly recur. When combined with standard therapy, immunotherapies targeting PD-1/PD-L1 inhibition and subsequent T cell activation have improved overall survival in SCLC patients. However, the overall outcome of this tumor type remains limited, and more effective therapies to boost the activity of T cells or other immune cells are still needed.

Researchers investigated whether SCLC tumor irradiation could be combined with CD47 blockade to improve antitumor responses. First, the researchers implanted a mouse SCLC cell line into the lateral abdomen of NSG mice, which lack functional T, B, and NK cells but have functional monocytes and macrophages. The researchers discovered that 5 Gy irradiation inhibited tumor growth and 10 Gy irradiation nearly eradicated tumors in this case. Based on this observation, the researchers conducted additional experiments with a single component dose of 5 Gy to determine additional anti-tumor effects of the combination therapy.

CD47-blocking antibodies had little effect on tumor growth when used alone, most likely due to cross-reactivity with CD47 expressed on erythrocytes and other cells in vivo, with fewer antibody molecules capable of binding to SCLC cells in mice. The combination treatment of irradiation and CD47 blockade, on the other hand, significantly inhibited tumor growth. When compared to treatment alone, enhanced tumor suppression in combination therapy was associated with an increase in macrophage infiltration of the tumor microenvironment.

Again, as expected, CD47 knockdown SCLC cells were phagocytosed more efficiently by primary macrophages in culture and formed smaller tumors, which were enhanced further by radiation treatment. Irradiation in combination with anti-human CD47 antibodies improved the antitumor effects of both human SCLC xenograft models, with increased macrophage infiltration and no significant weight loss.

Finally, the researchers discovered that pharmacological or genetic CD47 inhibition in subcutaneous mouse tumors grown in immunocompetent mice resulted in enhanced tumor suppression after irradiation, indicating that the observed antitumor effects are unaffected by the presence of T, B, or NK cells. In SCLC mice and human preclinical models, CD47 inhibition improves the antitumor effects of local radiotherapy.

The study demonstrates the potential for non-dependent distant compartmentalizing effects of T cells via the combination of radiotherapy and CD47 blockade, but further interactions between innate and adaptive immune responses may exist, and clinical studies are required. T cell and macrophage activation may enhance radiotherapy's systemic antitumor effects in patients.

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