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Abstract：
BACKGROUND: In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies.
METHODS: We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC.
RESULTS: Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment.
CONCLUSIONS: RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
METHODS: We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC.
RESULTS: Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment.
CONCLUSIONS: RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
摘要：
背景：在透明细胞肾细胞癌（ccRCC）中，一线治疗结合了纳武单抗（抗PD-1）和伊匹单抗（抗CTLA4），产生长期缓解，但只有40%的成功率。我们的研究探索了通过同时使用CXCR2抑制剂和免疫疗法来增强ccRCC治疗的潜力。
方法：我们分析了ELR+CXCL水平及其与免疫治疗期间患者生存的相关性。RCT001是一种独特的CXCR2抑制剂，对其作用机制进行了研究，特别是它对人类原代巨噬细胞的影响。我们在存在人PBMC的ccRCC和人ccRCC的小鼠模型中测试了RCT001与免疫疗法组合的协同影响。
结果：发现ELR+CXCL细胞因子水平升高与免疫治疗期间总生存率降低相关。RCT001，我们的优化化合物，充当反向激动剂，有效抑制血管生成和降低原代ccRCC细胞的活力。它重定向M2样巨噬细胞而不影响针对肿瘤的M1样巨噬细胞极化。在老鼠模型中，RCT001通过抑制肿瘤相关的M2巨噬细胞和肿瘤相关的中性粒细胞来增强抗CTLA4+抗PD1的功效。它还影响了CD4T淋巴细胞的激活，减少免疫耐受淋巴细胞，同时增加激活的自然杀伤细胞和树突状细胞。当RCT001与抗PD-1治疗组合时,在人RCC肿瘤中观察到类似的有效性。
结论：RCT001，通过其独特的机制抑制CXCR2，有效抑制ccRCC细胞增殖，血管生成,和M2巨噬细胞极化。这种优化增强了免疫疗法的功效，并有望显着改善转移性ccRCC患者的生存前景。
方法：我们分析了ELR+CXCL水平及其与免疫治疗期间患者生存的相关性。RCT001是一种独特的CXCR2抑制剂，对其作用机制进行了研究，特别是它对人类原代巨噬细胞的影响。我们在存在人PBMC的ccRCC和人ccRCC的小鼠模型中测试了RCT001与免疫疗法组合的协同影响。
结果：发现ELR+CXCL细胞因子水平升高与免疫治疗期间总生存率降低相关。RCT001，我们的优化化合物，充当反向激动剂，有效抑制血管生成和降低原代ccRCC细胞的活力。它重定向M2样巨噬细胞而不影响针对肿瘤的M1样巨噬细胞极化。在老鼠模型中，RCT001通过抑制肿瘤相关的M2巨噬细胞和肿瘤相关的中性粒细胞来增强抗CTLA4+抗PD1的功效。它还影响了CD4T淋巴细胞的激活，减少免疫耐受淋巴细胞，同时增加激活的自然杀伤细胞和树突状细胞。当RCT001与抗PD-1治疗组合时,在人RCC肿瘤中观察到类似的有效性。
结论：RCT001，通过其独特的机制抑制CXCR2，有效抑制ccRCC细胞增殖，血管生成,和M2巨噬细胞极化。这种优化增强了免疫疗法的功效，并有望显着改善转移性ccRCC患者的生存前景。
