Intratumoural and peripheral blood lymphocyte subsets in patients with metastatic renal cell carcinoma undergoing interleukin-2 based immunotherapy: association to objective response and survival

Abstract

The aim of the present study was to analyse lymphocyte subsets in consecutive peripheral blood samples and consecutive tumour tissue core needle biopsies performed before and during interleukin-2 based immunotherapy, and to correlate the findings with objective response and survival. Twenty-six patients with metastatic renal cell carcinoma were treated with low dose s.c. interleukin-2, interferon-α and histamine. A total of 250 blood samples and 62 core needle biopsies from 23 and 19 of these patients, respectively, were analysed. After 2 weeks of treatment, a significant positive correlation between absolute number of peripheral blood lymphocytes ( P =0.028), CD3 ( P =0.017), CD57 ( P =0.041) and objective response was demonstrated. There was no correlation between any peripheral blood leukocyte subsets and survival. Cytotoxicity of peripheral blood mononuclear cells was not correlated to objective response or survival. Within the tumour tissue at baseline, a significant positive correlation between CD4 ( P =0.027), CD8 ( P =0.028), CD57 ( P =0.007) and objective response was demonstrated. After one month of immunotherapy, a significant positive correlation between intratumoral CD3 ( P =0.026), CD8 ( P =0.015), CD57 ( P =0.009) and objective response was demonstrated. A significant positive correlation between intratumoral baseline CD4 ( P =0.047), baseline CD57 ( P =0.035), CD3 at one month ( P =0.049) and survival was demonstrated. These data provide novel in vivo evidence of the possible contribution of lymphocyte subsets in the tumour reduction in responding patients during interleukin-2 based immunotherapy. Confirmation of the results requires further studies including a larger number of patients. British Journal of Cancer (2002) 87 , 194–201. doi: 10.1038/sj.bjc.6600437 www.bjcancer.com © 2002 Cancer Research UK

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

“…Our tumour tissue analyses demonstrated only modest reduction in the number of proliferating tumour cells induced by IFN-a and IL-2, suggesting that immunotherapy reduces tumour size but has only limited effect on intrinsic tumour aggressiveness in vivo. We have previously demonstrated that localisation of CD4 þ , CD8 þ and CD57 þ lymphocytes to sites of tumour is a requisite for the response to therapy (Donskov et al, 2002a), thus hypothesising that the antitumour activity of IFN-a in vivo is primarily cellular immune mediated. This hypothesis is in accordance with previous in vitro findings (Kosmidis et al, 1992;Tsavaris et al, 1996).…”

“…Whereas cellular immune effector mechanisms are considered to be the most important mediators of IL-2 antitumour activity (Rubin et al, 1989;Donskov et al, 2002a), IFN-a in addition (Kosmidis et al, 1992;Tsavaris et al, 1996;Donskov et al, 2002a) is considered to exert antiproliferative (Grander et al, 1997) and differentiationinducing effects on the tumour cells (Pfeffer et al, 1998). In vitro, a direct antiproliferative effect on renal tumour cells has been demonstrated for IFN-a (Nanus et al, 1990), whereas IL-2 has no direct impact on cancer cells (Rosenberg, 2001).…”

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

“…The cytotoxic activity of the tumor-infiltrating lymphocytes mainly resides in the CD16 dim NK cell population that expresses CD94/NKG2A more strongly than the peripheral NK cells (Schleypen et al, 2003(Schleypen et al, , 2006. Moreover, the response to IL2 in RCC patients can be correlated with the extent of tumor infiltration by NK cells, showing NK cell importance in tumor control (Donskov et al, 2002).…”

Monocytes and neutrophils as ‘bad guys’ for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma – results from a randomised phase II trial

“…Thus, NK and T cells remain viable and responsive to interleukin-2 (IL-2) Asea et al, 1996). IL-2 has no direct impact on tumour cells (Rosenberg, 2001) but requires NK and T-cells for tumourlysis (Donskov et al, 2002a(Donskov et al, , 2004a. Thus, the addition of histamine may potentially improve the efficacy of IL-2.…”