Circulating immune markers in advanced renal cell carcinoma during immunotherapy with interferon gamma

Abstract

Circulating immune markers sICAM-1, sELAM-1, sMHC-I, beta 2-MG, sCD4 and sCD8 were evaluated prior to and during immunotherapy with biologically active doses of interferon gamma (IFN-gamma) in 16 patients with advanced renal cell carcinoma (RCC) over a period of 12 months. Compared to 20 healthy controls, significantly (P < 0.01) elevated baseline levels of circulating adhesion molecules sICAM-1 (mean 1166 vs 230 ng/ml) and sELAM-1 (70 vs 17 ng/ml) were found in all patients. Compared to responders (n = 2) or patients with stable disease (n = 2), progressive disease during therapy (n = 12) was associated with significantly (P < 0.05) higher mean concentrations of sICAM-1 (1574 vs 962 ng/ml) and sELAM-1 (86 vs 46 ng/ml). Pretherapeutic and intratherapeutic levels of sMHC-I among the RCC patients were significantly (P < 0.05) lower than among the controls (0.41 vs 0.8 ng/ml). sCD4 levels clearly showed the same tendency (24 vs 33 U/l). sCD8 baseline levels, by contrast, were significantly (P < 0.05) elevated (564 vs 336 U/l), reflecting either activation of the NK-cell subset or increased synthesis of CD8+ T-suppressor cells. Again, significantly (P < 0.05) higher intratherapeutic sCD8 concentrations were observable with progressive disease than with response to therapy or stable disease (721 vs 355 U/l). Interestingly, although the biologically active dose of IFN-gamma was defined by an increase in beta 2-MG release of at least 30% within 48 h after injection, none of the other markers showed any significant alteration following IFN-gamma administration, suggesting that IFN-gamma in vivo does not produce changes in circulating markers of activation that might be expected on the basis of its effects in vitro. The finding of significantly elevated concentrations of sICAM-1, sELAM-1 and sCD8 in the presence of low sCD4 and sMHC-I levels might be of clinical significance for indicating ongoing tumor progression.

Low on-treatment levels of serum soluble CD8 (sCD8) predict better outcomes in advanced non-small cell lung cancer patients treated with atezolizumab

“…We demonstrated that NSCLC patients who achieved long-term disease control presented lower serum sCD8 at the end of cycles 2–4. Although no published papers assessed the circulating sCD8 levels in cancer patients on PD-1/PD-L1 inhibitors, lower baseline sCD8 was previously shown in responders to immunotherapy with interferon-alpha (IFN-α) [ 36 ] and higher on-treatment sCD8—in patients with progressive disease dosed with IFN-γ [ 37 ]. In contrast, other authors highlighted better outcomes with a higher baseline sCD8 [ 38 ] or a higher increase in serum sCD8 during treatment [ 39 ], but those patients were dosed with a different drug (interleukin-2, IL-2).…”

“…The ambiguous results could suggest that the direction of correlation between sCD8 levels and immunotherapy success is not that obvious and might depend on additional factors, such as a type of malignancy and the used immunomodulator. Accordingly, higher sCD8 levels were favorable in melanoma and renal cell carcinoma patients but only during treatment with IL-2 [ 38 , 39 ] and not with IFN-γ [ 37 ]. Moreover, different behavior of sCD8 was noted during immunotherapy with various drugs: there was a trend toward the sCD8 levels increasing after dosing with recombinant IL-2 [ 31 , 39 – 41 ] or successful treatment with IFN-γ [ 37 ], but a similar trend was not observed in our cohort (Fig.…”

“…Accordingly, higher sCD8 levels were favorable in melanoma and renal cell carcinoma patients but only during treatment with IL-2 [ 38 , 39 ] and not with IFN-γ [ 37 ]. Moreover, different behavior of sCD8 was noted during immunotherapy with various drugs: there was a trend toward the sCD8 levels increasing after dosing with recombinant IL-2 [ 31 , 39 – 41 ] or successful treatment with IFN-γ [ 37 ], but a similar trend was not observed in our cohort (Fig. 2 ).…”