Recently, novel molecular targeted agents markedly changed the treatment of renal cell carcinoma (RCC), with promising results. However, there is little understanding of how these agents affect immune cell populations in RCC, an immunogenic tumor. Therefore, we investigated the changes in the peripheral blood immune cells in 58 RCC patients during the first 4 weeks of treatment with sorafenib, sunitinib, everolimus, or temsirolimus and evaluated whether these changes were associated with clinical outcomes. The immunological parameters were the proportion of type-1 (Th1) and type-2 (Th2) T cells, regulatory T cells (Treg), mature dendritic cells, and the neutrophil-to-lymphocyte ratio (NLR). The changes in these immune cells varied with the agents and the clinical response, dichotomized by the median progression-free survival (PFS) time (PFS-short or PFS-long). A significant decrease in the Th1/Th2 ratio was seen after sunitinib treatment only in the PFS-short group, suggesting a shift toward Th2 that down-regulates host immunity. The NLRs indicative of the balance between host immunity and cancer-related inflammation were consistently lower in the PFS-long group than in the PFS-short group, suggesting that lower NLR is associated with better clinical response. Only sunitinib decreased NLR remarkably regardless of PFS status, which may favor anti-tumor immunity. When patients were dichotomized by the cutoff values, Th1/Th2 ratio was not associated with PFS in any targeted therapy, while lower pre-treatment NLR was associated with longer PFS in each targeted therapy. In addition, in RCC patients given sequential targeted therapy, those with a lower baseline NLR survived significantly longer compared with the counterparts. Moreover, those whose baseline NLR was sustained low during the initial therapy survived the longest. Our results suggest the diverse changes in host immune cells in RCC patients during targeted therapy. The changes in NLR during the early phase of targeted therapy may be a powerful discriminator of who will benefit from the subsequent treatment.

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA‐4, PD‐1, and PD‐L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti‐CTLA4, anti‐PD‐1, or anti‐PD‐L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD‐L1 and B7‐H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF‐targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD‐1, PD‐L1, B7‐H3, B7‐H4, and CTLA‐4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD‐L1 and B7‐H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti‐VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD‐L1 and B7‐H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti‐VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs.

Background: To elucidate whether Hand -Foot skin reaction could become a biomarker of clinical outcome in patients with metastatic renal cell carcinoma treated with sorafenib, we retrospectively examined the association between the Hand -Foot skin reaction and the clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib. Methods: Thirty-six Japanese metastatic renal cell carcinoma patients treated with sorafenib were enrolled and divided into the groups with or without Hand -Foot skin reaction. Patient characteristics, best tumor response, progression-free survival and adverse events were investigated and compared between these two groups. Results: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients was observed at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification, and with Eastern Cooperative Oncology Group Performance Status of one or less, prior nephrectomy, higher hemoglobin, lower lactate dehydrogenase and lower C-reactive protein. The mean best tumor response was significantly better in the group with Hand -Foot skin reaction (216.7%) than that in the group without it (17.9%; P , 0.001). The median progression-free survival was significantly longer in the group with Hand -Foot skin reaction (4.6 months) than that in the group without it (1.5 months; P ¼ 0.002). In multivariate analysis, only Hand -Foot skin reaction was shown to be a predictive factor of progression-free survival (hazard ratio 0.312, P ¼ 0.010). Conclusions: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients emerged at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification and was significantly associated with best tumor response and progression-free survival, suggesting that Hand -Foot skin reaction might be an independent predictive factor for clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib.

The neuropeptide precursor ProGRP is a distinct serum marker that is useful to know the NE milieu and provides prognostic information in patients with advanced prostate cancer. Standard therapy for metastatic prostate cancer may make progress when further studies will clarify the causative link between serum ProGRP level and androgen-independent disease progression.

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