Macrophage-mediated abscopal effects of radiation therapy

Radiation therapy is a mainstay of cancer treatment, with more than 50% of all cancer patients receiving radiation during the course of their disease. Tumor irradiation can activate both innate and adaptive immune responses, and these responses can be pro- or anti-tumor growth . These observations have led to the search for antitumor approaches combining radiotherapy and specific immunotherapies, most commonly strategies promoting the systemic activation of T cells. Thus far, however, many cancer patients still suffer from local recurrence and/or untreatable metastatic disease after radiotherapy. Here we combine radiotherapy with activation of macrophage-mediated phagocytosis via blockade of the ?don?t-eat-me? cell surface molecule CD47 in small-cell lung cancer (SCLC), a highly metastatic form of lung cancer for which treatment options remain limited. We found that irradiation of SCLC cells in culture results in the secretion of inflammatory cytokines that results in increased migration and phagocytosis by macrophages. In vivo, CD47 blockade potently enhances the local antitumor effects of radiation therapy in murine and human pre-clinical models of SCLC. Strikingly, CD47 blockade also stimulates abscopal antitumor effects inhibiting the growth of non-irradiated SCLC tumors in mice receiving radiation. Similar abscopal antitumor effects were observed in colon cancer and lymphoma models. Surprisingly, these abscopal effects are completely independent of T cells but require macrophages that migrate into the non-irradiated tumor sites in response to inflammatory signals mediated by radiation and are locally activated by CD47 blockade to eliminate cancer cells. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in cancer patients who suffer from metastatic disease. Single-cell RNA sequencing (scRNA-seq) of CD45+ leukocytes at non-irradiated sites in mice treated either with radiotherapy alone or radiotherapy and CD47

放射治疗是癌症治疗的核心支柱手段之一，超过50%的癌症患者在病程中会接受放射治疗。肿瘤照射可激活固有免疫与适应性免疫应答，这类应答既可促进也可抑制肿瘤生长。基于上述观察，学界开始探索将放射治疗与特定免疫治疗相结合的抗肿瘤策略，其中最常见的是促进T细胞全身激活的方案。然而迄今为止，仍有众多癌症患者在接受放射治疗后出现局部复发和/或无法治疗的转移性疾病。
本研究将放射治疗与通过阻断“别吃我”（don’t-eat-me）细胞表面分子CD47来激活巨噬细胞介导的吞噬作用相结合，应用于小细胞肺癌（small-cell lung cancer, SCLC）——一种转移性极强且治疗选择有限的肺癌亚型。我们发现，体外培养的小细胞肺癌细胞经照射后会分泌炎症因子，进而增强巨噬细胞的迁移能力与吞噬活性。在体内实验中，CD47阻断可在小细胞肺癌的小鼠及人类临床前模型中，强效增强放射治疗的局部抗肿瘤效果。
值得注意的是，CD47阻断还可诱导远隔抗肿瘤效应，抑制接受放射治疗的小鼠体内未照射的小细胞肺癌肿瘤生长。此类远隔抗肿瘤效应在结肠癌与淋巴瘤模型中也同样被观测到。令人意外的是，这些远隔效应完全不依赖T细胞，而是需要巨噬细胞：它们会响应放射介导的炎症信号迁移至未照射的肿瘤部位，并在CD47阻断的作用下被局部激活，从而清除癌细胞。
放射治疗联合CD47阻断所介导的抗肿瘤巨噬细胞全身激活，对于罹患转移性疾病的癌症患者可能尤为重要。本研究对仅接受放射治疗，或联合放射治疗与CD47阻断的小鼠体内未照射部位的CD45阳性白细胞进行了单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）。