Serum Cytokine Profile in Metastatic Renal Cell Carcinoma (mRCC) Patients Treated with Immunotherapy

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Background: The in vivo cytokine microenvironment plays a pivotal role in response to immunotherapy. We analyzed the serum cytokine levels in mRCC patients enrolled in a Phase II trial using intranodal DC vaccine combined with Interleukin-2 and Interferon-α therapy in metastatic renal cell carcinoma (RCC) patients.
Methods:
Pre- and mid-treatment serum samples from all 18 study patients were analyzed for cytokine levels. Patients were divided into responders (R; complete and partial; n=9) and non-responders (NR; stable and progressive disease, n=9) and compared with healthy aged matched donors (HD, n=5). Serum was analysed for 27 cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Basic FGF, Eotaxin, G-CSF, GM-CSF, IFN-gamma, IP-10, MCP-1 (MCAF), MIP-1alpha, MIP-1 beta, PDGF-BB, RANTES, TNF-alpha, VEGF) using the Luminex® fluorescent bead technology. Student t-Test or Whitney rank sum test was used to test for differences between groups and p<0.05 was considered significant.
Results:
IL-4, IL-6, IL-7, IL-8, IL-12, IL-13, G-CSF, IFN-gamma, IP-10 (Inferferon gamma inducible protein), MIP-1a, MIP-1b, PDGF, RANTES, VEGF showed significantly higher values in RCC patients than in HD. Treatment resulted in significantly higher serum levels of the anti-angiogenetic factor IP-10 (125.8±70.6 vs 520.6±244.5, p:0.002). Responding patients showed higher levels of IP-10 pre-treatment than non-responding patients (169±68.3 vs. 82.5±44.5, p:0.002). Interestingly, inflammatory cytokines (IL2, IL7, IL8, IL9, IL13, IL17, G-CSF, GM-CSF, TNF-alpha, RANTES, MIP 1-alpha) decreased during treatment in responding patients and increased in non-responding patients (ratio NR/R pre :0.45±0.58 vs post: 2.02±3.60, p:0.008).

Cytokin	Healthy donors (HD) Mean ± StD /pg/ml	Patients pre-treatment Mean ± StD /pg/ml	Patients post-treatment Mean ± StD /pg/ml	p-value patients pre vs HD Mean ± StD /pg/ml
IL-1 beta	*	1.4 ±2.1	3.3 ±3.4	0.2840
IL-2	*	183.1 ±518.0	97.9 ±259.9	0.7240
IL-4	1.2 ±0.4	2.9 ±1.0	2.9 ±0.8	0.0030
IL-5	*	2.5 ±3.3	4.5 ±4.8	0.1710
IL-6	3.6 ±0.5	20.5 ±22.5	16.9 ±14.2	0.0020
IL-7	3.6 ±3.9	11.0 ±3.2	11.3 ±4.9	0.0030
IL-8	3.8 ±8.5	13.8 ±14.3	26.6 ±30.2	0.0020
IL-9	*	546.3 ±1545.0	288.8 ±608.9	0.7240
IL-10	*	136.6 ±384.8	108.8±305.2	0.2840
IL-12	*	47.8± 127.8	28.8 ±68.9	0.0300
IL-13	*	80.5 ±201.5	60.4 ±120.6	0.0060
IL-17	*	13.8 ±38.9	32.4 ±60.7	0.7240
Eotaxin	*	20.8 ±34.7	22.0 ±39.4	0.2840
G-CSF	4.4 ±6.1	22.1 ±15.6	22.0 ±11.1	0.0060
GM-CSF	*	6.5 ±18.4	6.8 ±12.7	0.7240
IFN-gamma	7.0 ±3.1	21.5 ±14.4	21.5 ±11.1	0.0020
IP-10	8.8 ±19.7	125.8 ±70.6	520.6 ±244.5	0.0020
MIP-1a	0.4 ±0.9	5.9 ±4.6	7.8 ±4.7	0.0020
MIP-1b	8.0 ±17.9	95.3 ±35.9	134.5 ±58.6	0.0020
PDGF	1100.0 ±764.3	5862.5 ±2291.5	6077.1 ±3157.2	0.0010
RANTES	2624.8 ±772.9	5407.5 ±992.9	5401.3 ±843.4	<0.001
TNF-alpha	*	13.4 ±32.5	24.1 ±38.5	0.5240
VEGF	9.6 ±8.4	127.9 ±99.2	164.0 ±100.1	0.0020

Conclusions: The data support the previously reported significant clinical success of this treatment strategy. In addition, it may lead to the development of a group of biomarkers able to predict response to immunotherapy.

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