In a pooled analysis of the SWOG and EORTC studies, cytoreductive nephrectomy combined with cytokines was confirmed to be able to prolong the overall survival of patients, compared with cytokine therapy alone [5, 11, 12]. Cytoreductive nephrectomy was the standard of care for metastatic renal cell carcinoma before the era of targeted therapy. Several retrospective studies have suggested that in the era of targeted therapy, there may be survival benefit to patients from cytoreductive nephrectomy. In a retrospective study analysis, 314 patients were recruited, 201 patients undergoing CN and 113 patients not undergoing CN, and observed a median OS of 19.8 months versus 9.4 months [13]. Subsequently, similar conclusions have been reached in other retrospective clinical studies, in the SEER database, and in the National Cancer database with large-sample data analysis [14–16]. However, CARMENA study performed a prospective multicenter clinical study in patients with metastatic clear cell carcinoma, and concluded that monotherapy with sunitinib was non-inferior to nephrectomy plus sunitinib for overall survival, especially for patients at intermediate and poor risk for MSKCC score [6]. SURTIME study in the same year explored the systemic therapy of sunitinib and the timing of nephrectomy, and delayed cytoreductive nephrectomy was found not to improve the 28-week progression-free rate (PFR), meanwhile, patients with delayed cytoreductive nephrectomy had a longer OS [17]. Both studies were prospective, randomized controlled trials, but the subtype of patients was clear cell carcinoma only. In CARMENA study, only intermediate and poor risk patients were enrolled, and no favorable risk patients were available. Only 99 patients were enrolled in the SURTIME study, which was far below the estimated sample size. Therefore, both studies have some limitations, and their reference for clinical application is limited.
Vascular endothelial growth factor (VEGF) promotes immune suppression by enhancing the influx of suppressive cell types into the tumor microenvironment (TME), modulating the activity of myeloid-derived suppressor cells (MDSCs) and Treg cells, inhibiting the maturation of dendritic cells (DCs) [18, 19].Small molecule TKI plays an anti-tumor role by inhibiting VEGF receptor to reduce tumor angiogenesis and immunosuppression. However, only treatment of mRCC with TKIs was prone to drug resistance, and PFS was only approximately 6 to 11 months [20, 21]. Immune checkpoint inhibitors block the binding of immunosuppressive molecules to restore anti-tumor responses. In preclinical theory, TKIs in combination with immune checkpoint inhibitors were reported to have a synergistic anti-tumor effect [22]. KEYNOTE 426 and CLEAR studies later confirmed that immunotherapy in combination with targeted therapy was significantly superior to targeted therapy alone [23, 24]. Immunotherapy combined with tyrosine kinase inhibitors (TKIs) was approved by the FDA for the treatment of mRCC in 2019 [25]. As the types of systemic therapy change, the re-evaluation of the role of nephrectomy in mRCC is important.
In this study, we retrospectively analyzed 165 patients with mRCC treated with immunotherapy in combination with targeted therapy. Patients were divided into two groups according to whether they underwent nephrectomy or non-nephrectomy prior to combined immune-targeted therapy. However, it is important to note that the median PFS in the nephrectomy group was 3.6 months longer than that in the non-nephrectomy group, and an HR of 0.476 (95% CI 0.323–0.701, p = 0.0002), the 12- and 18-month PFS rates in the nephrectomy group were significantly higher than those in the non-nephrectomy group. Preliminary OS analysis suggested that the overall survival of the nephrectomy group was significantly better than that of the non-nephrectomy group, although the ORR and DCR in the nephrectomy group were slightly higher than those in the non-nephrectomy group, but the difference did not reach statistically significant. The two groups were comparable in terms of safety. Multivariate analysis showed that nephrectomy, clear cell carcinoma and oligo-organ metastasis were independent favorable prognostic factors for mRCC with immune-targeted therapy.
The human immune system is also a double-edged sword for tumors, the immune system not only inhibit tumor growth but also promote tumor progression by alterations in gene mutations, tumor microenvironment, and cell signaling pathways [26].TCGA database transcriptome analysis identified that clear cell renal cell carcinoma enriched immune infiltration and T cell infiltration [27].Studies have confirmed that the immune components and functions of primary and metastatic renal cell carcinoma roughly overlap[28], however, the higher expression of PD-L1 and a lower CD8 to Foxp3 T cell ratio were found in metastatic lesions compared with matched primary tumor tissue[29].Several hypotheses explained the potential mechanisms by which nephrectomy confers survival benefits. First, increased apoptosis of lymphocytes [30], impairment of T-cell receptors and signal transduction[31], and dysfunction of tumor-infiltrating lymphocytes [32]were observed in renal cell carcinoma tissues. Primary renal cell carcinoma has also been shown to produce high levels of proinflammatory cytokines and T-cell inhibitory cytokines such as interleukin 8 (IL-8), IL-6, transforming growth factors, and weaken the immune response[33].Second, Myeloid cells lead to tumor progression and metastasis by promoting angiogenesis and vasculogenesis as well as inhibiting anti-tumor immunity. Accumulation of tolerogenic DCs and the elevated levels of circulating MDSCs in RCC are detrimental to the immune microenvironment and worsen the metastatic lesions burden[34–36].Moreover, the expression of immune response target factors, such as CTLA-4,B7-H1,B7-H3,B7-H4 and PD-1 on the surface of tumor cells and effector T cells can be negatively regulated by these immunosuppressive factors and cells, resulting in tumor cells immune escape[37, 38].Therefore, primary renal tumor resection reduces the burden of immunosuppressive factors and cells, enhances the immune response.
Renal cell carcinomas are heterogeneous tumors with different immunogenicity characteristics. Clear cell renal cell carcinoma (ccRCC) are characterized by rich leukocyte infiltrates, which often consist of CD8+T cells, CD4+ T cells, natural killer cells and myeloid cells [39, 40].High proliferative activity CD8 + T cells reflect excellent antitumor immunity and are associated with longer survival [41].Thompson et al first reported the expression of PD-L1 in ccRCC, and 66.7% of 196 clear cell carcinoma samples had PD-L1 expression > = 5% [38]. In another study, tumor cell PD-L1 expression was found to be 10.9% in 101 non-ccRCC patients [42].Although PD-L1 positive tumors are associated with a worse clinicopathological classification, such advanced TNM stage and higher Fuhrman grade, they are also one of potential biomarkers for immunotherapy [43]. A phase II trial of cabozantinib plus nivolumab in patients with non-ccRCC found that the objective response rate for patients with papillary, unclassified, or translocation-associated RCC (n = 40) was 47.5%, with mPFS 12.5months, in patients with chromophobe RCC (n = 7), no response was observed [44]. Patients enrolled in KEYNOTE 426 were clear cell renal cell carcinoma, with an ORR of 59.3% and an mPFS of 15.1m. Analysis of existing clinical research data suggests that the efficacy and survival of patients with clear cell renal cell carcinoma who receive combination targeted immunotherapy is superior to that of non-ccRCC. The ccRCC group had better PFS than the non-ccRCC group in this study, which may be related to tumor-infiltrating T lymphocytes activity and PD-L1 expression. The factors that affect the efficacy of immune-targeted combination therapy are complex, including immune evasion, metabolic reprogramming and the immune microenvironment in addition to TILS and PD-L1 [45, 46]. Thus, the efficacy of immunotherapy in combination with targeted therapy in both clear cell carcinoma and non-clear cell carcinoma requires further investigation.
We recognize the limitations of non-randomized, retrospective, analyses. Data were obtained from three centers, but the sample size was limited and OS maturity was lacking, with over half of patients failing to progress to OS. Further, there was heterogeneity between the two groups of patients with combination immune-targeted drugs, although the characteristics of the two groups were balanced. Depth of response was not analyzed, due to limited data. Outcomes would benefit from longer follow-up.