Synergistic treatment strategy: combining CAR-NK cell therapy and radiotherapy to combat solid tumors

Abstract

Immunotherapy, notably chimeric antigen receptor (CAR) modified natural killer (NK) cell therapy, has shown exciting promise in the treatment of hematologic malignancies due to its unique advantages including fewer side effects, diverse activation mechanisms, and wide availability. However, CAR-NK cell therapies have demonstrated limited efficacy against solid tumors, primarily due to challenges posed by the solid tumor microenvironment. In contrast, radiotherapy, a well-established treatment modality, has been proven to modulate the tumor microenvironment and facilitate immune cell infiltration. With these observations, we hypothesize that a novel therapeutic strategy integrating CAR-NK cell therapy with radiotherapy could enhance the ability to treat solid tumors. This hypothesis aims to address the obstacles CAR-NK cell therapies face within the solid tumor microenvironment and explore the potential efficacy of their combination with radiotherapy. By capitalizing on the synergistic advantages of CAR-NK cell therapy and radiotherapy, we posit that this could lead to improved prognoses for patients with solid tumors.

Keywords: chimeric antigen receptor; natural killer cells; radiotherapy; solid tumors; tumor microenvironment.

Figure 1

The killing mechanism of CAR-NK. 1.Intrinsic direct killing mechanism: NK cells directly kill tumor cells through the following mechanisms: Releasing perforin and granzyme B to directly induce tumor cell lysis; Secreting cytokines TNF-α and IFN-γ to induce apoptosis in tumor cells; Mediating tumor cell apoptosis through the FasL/TRAIL pathway; Exerting antibody-dependent cellular cytotoxicity (ADCC) mediated by CD16. 2. Intrinsic indirect killing mechanism NK cells have the ability to secrete chemokines, recruiting T cells, DC cells, and other immune cells to engage in collaborative cytotoxicity against tumor cells. 3. CAR dependent mechanism The CAR structure can recognize tumor-specific antigens, thereby activating NK cells to kill tumor cells by releasing perforin and granzyme B, among others. The figure is created with BioRender.com. CAR, chimeric antigen receptor; DC, dendritic cell; NK, natural killer; FasL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon-gamma.

Figure 2

Role of NK cells in radiotherapy-induced antitumor immunity. 1.Following radiotherapy, the dsDNA of tumor cells is exposed to the cytoplasm to activate the cGAS/STING pathway, initiate type I interferon response, induce the secretion of some chemotactic factors, and recruit NK cells into the tumor microenvironment. 2. Radiotherapy can upregulate the expression of several adhesion molecules like ICAM-1 and VCAM-1, which increases the adhesion of NK cells to the endothelial surface. 3. After radiotherapy, tumor cells exhibit an upregulation in stress proteins MICA/B and ULBP1-6, which can effectively activate NK cells and initiate an immune response against the tumor. 4. Radiotherapy induces ICD in tumor cells, leads to the release of DAMPs, and activates NK cells. 5. Radiotherapy plays a pivotal role in decreasing tumor burden and creating a favorable environment for NK cell infiltration. The figure is created with BioRender.com NK, natural killer; cGAS, cyclic GMP-AMP synthase; STING, stimulator of interferon genes; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; MIC, major histocompatibility complex class I chain-related protein. ULBP, UL16-binding protein; ICD, immunogenic cell death; DAMPs, damage-associated molecular patterns.

Figure 3

Timing of radiotherapy intervention. 1. Low-dose radiotherapy induces NK cell expansion. 2. Low-dose radiotherapy stimulates NK cells to secrete INF-γ and TNF-α. 3. Radiotherapy reduces tumor burden and facilitates CAR-NK infiltration. 4. Radiotherapy-induced lymphopenia provides space for CAR-NK expansion. 5. Radiotherapy induces chemokine release and attracts CAR-NK to the tumor. CAR, chimeric antigen receptor; NK, natural killer; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon-gamma.