• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • IP CXCL is an inflammatory chemokine that is produced


    IP-10/CXCL10 is an inflammatory chemokine that is produced by various Y-27632 including leukocytes and acts as a potent chemoattractant for T cells. IP-10 has been reported to create an immune suppressive microenvironment mobilizing immune suppressive cells such as regulatory T cells (Tregs) [25,26]. It has been reported that NSCLC cells express IP10 [27,28], thus Tregs may be attracted by the action of IP-10 derived from tumor cells followed by the creation of an immune suppressive microenvironment (Fig. 4). From our data, no correlations were observed between follistatin and IP-10 levels and little has been reported on the association between follistatin and IP-10. The crosstalk between follistatin and IP-10 should be investigated to further clarify the mechanisms of clinical benefit from nivolumab treatment in patients with lung cancer. Sanmamed et al. reported that changes in IL-8 levels in responders could predict responsiveness to anti-PD-1 treatment in NSCLC and melanoma [17]. In the present study, a similar trend was observed in terms of tumor response and durable clinical benefit (Supplementary Fig. 1E and Fig. 4), but this was not confirmed by a multivariate analysis (Table 2). A recent study has shown that an IL-8 blocking antibody decreased MDSCs in the tumor tissue of an experimental breast cancer xenograft model [29]. Given that tumor derived IL-8 attracts MDSCs and that intra-tumor IL-8 levels are associated with the accumulation of MDSCs, IL-8 could directly control the establishment of the tumor immune microenvironment [30,31]. Therefore, serum IL-8 levels may have the potential to identify patients that are likely to benefit from nivolumab treatment in advanced NSCLC and so should be further investigated. The detailed mechanisms of irAEs still remain elusive [13]. One of the mechanisms was reported by Amarnath et al. using a mouse model of graft-versus host disease (GVHD) where they reported that Tregs mediate immune suppression in vivo by modulating the PD-1 pathway [32]. We observed the potential involvement of RANTES in irAE caused by nivolumab treatment in patients with NSCLC and some reports have shown that RANTES is one of the serum proteins relevant to the development of GVHD [[33], [34], [35]]. RANTES functions as a chemoattractant of a variety of immune cells such as activated T cells and a knockout of the CCL5 receptor reduces both the severity of both systemic and target organ GVHD [35], supporting our findings that RANTES may be a potential biomarker for the onset of irAE (Fig. 4). Therefore, surveillance of these proteins levels may be helpful in predicting the onset of irAE. However, we did not find any difference in the baseline protein levels except at week 4. This indicates that it is not possible to predict irAE onset before initiation of nivolumab treatment and that careful monitoring of the serum protein levels during treatment will be required. It is, however, still beneficial to identify patients who are more likely to develop irAEs and this should be further studied in a larger cohort. Several studies have reported that the onset of irAEs is correlated with the efficacy of nivolumab treatment in patients with advanced NSCLC [[14], [15], [16]]. We expected that there would be some overlapping proteins between efficacy and irAE onset. However, we did not identify any overlapping proteins associated with both nivolumab efficacy and irAE onset. Therefore, there is a possibility that the efficacy and irAEs induced by nivolumab may be regulated differently in a spatiotemporal manner (Fig. 4). Indeed, one of the patients who developed irAE- was administered nivolumab only once and was treated with corticosteroid immediately after irAE diagnosis. Although the patient was continuously under immune-suppression, the tumor response was maintained even after corticosteroid treatment. It has been reported that steroid use for the management of irAEs does not affect the efficacy of ipilimumab in melanoma patients [36]. On the other hand, it has been reported that baseline steroid levels negatively affect the efficacy of PD-1/PD-L1 blockade in patients with NSCLC [37]. Little is known about the association of mechanisms between the tumor response and irAEs induced by nivolumab and this needs to be further investigated.