Depleting SIRPα-deficient in macrophages activate tumor antigen-specific cytotoxic T cells

In a study that will be published in Nature Communications on May 28, 2021, a research team led by Dr. Yuan Liu from Georgia State University reports that intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells to eliminate various syngeneic cancers under radiotherapy.

As a major component of the suppressive tumor microenvironment, tumor-associated macrophages (TAMs) are generally regarded as facilitators of tumor progression. It has been shown that depleting TAMs can enhance the response of tumors to radiotherapy (RT). However, Yuan's group has shown that simply depleting signal-regulatory protein alpha (SIRPalpha) in macrophages can shift the post-radiation response of macrophages as well as the whole tumor microenvironment, from pro-tumor wound-healing to tumor elimination.

This work is important for the following reasons:

• 1)They report that depleting SIRPalpha on intratumoral macrophages revolutionizes RT to eliminate large, RT-resistant colorectal cancer, such as MC38, and pancreatic cancer, such as Pan02 and KPC, in mice. In general, when tumors are well-established or have progressed to an advanced stage, the RT-induced anti-cancer immune response is severely blunted. However, they show that, in stark contrast to wild-type mice in which RT fails to control tumor growth, a single fraction of RT (4, 8 or 15Gy) confers robust responses in Sirpalpha-/- mice.

• For tumors whose size ranged from 100mm3 to 400 mm3, each RT regimen well controlled tumor growth. For much larger tumors (400-600 mm3), RT still induced significant dose-dependent inhibition of tumor growth. Their study has identified SIRPalpha as a master regulator that controls macrophage immune responses and has also demonstrated that intratumoral injection of SIRPalpha-depleted macrophages combined with local radiation is a potentially effective strategy to treat different tumors.

  2)Through gene profiling and marker screening at the individual cell level, Yuan's team have analyzed alterations of the tumor microenvironment. Their results, surprisingly, indicate that SIRPalpha-depletion not only enhances phagocytosis of damaged tumor cells by macrophages under inflammatory stimulation, but also transforms the tumor microenvironment into a potent tumoricidal niche that is highly infiltrated by tumor-specific cytotoxic T cells (Tc), natural killer cells and tumor-damaging neutrophils, but also possesses significantly fewer regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

• In other words, in contrast to the conventional belief that blockade of SIRPalpha elicits tumor regression mainly by way of macrophage-mediated phagocytosis of cancer cells, their finding supports that RT-activated Sirpalpha-/- macrophages function less as enhanced phagocytes but more so as proinflammatory initiators and excellent antigen presenting cells that conduct immunogenic antigen presentation in situ to robustly activate tumor-specific memory T cells and T cell cytotoxicity.

  3)Employing an ex vivo and in vitro assay, they validate the in vivo observation that activated Sirpalpha-/- macrophages present tumor antigen to activate or 'call' tumor-specific CD8 T cells. Another piece of evidence supporting this notion is the abscopal effect elicited in irradiated Sirpalpha-/- mice. In rare instances, the abscopal effect can be observed when RT drives an immune response robust enough to control tumor burden outside the irradiated area. Yuan's team report that irradiation of primary lesions in Sirpalpha-/- mice has an abscopal effect on non-irradiated tumors and the magnitude of such an effect, as expected, is affected by the size of the abscopal lesions.