Intratumoral rhIL‐12 administration in head and neck squamous cell carcinoma patients induces B cell activation

Abstract

The objectives of this study were to investigate the effects of intratumorally (i.t.) administered recombinant human interleukin-12 (rhIL-12) on the distribution and function of B cells in the primary tumors, the locoregional lymph nodes and peripheral blood of head and neck squamous cell carcinoma (HNSCC) patients. The initial characterization of the patients participating in the phase Ib and phase II studies has previously been reported. After rhIL-12 treatment, fewer secondary follicles with a broader outer region of the mantle zones and an increase in interfollicular B-blasts were seen in the enlarged lymph nodes compared with control HNSCC patients. The size of the germinal center (GC) was diminished, partly due to a decrease in the number of CD571 GC cells that have been associated with immune suppression. These changes did not correlate with signs of apoptosis or CXCR5 expression by B cells. Strikingly, in 3 out of 4 IL-12 treated patients, increased IFN-c mRNA expression by B cells was detected. In addition, a highly significant IgG subclass switch was seen in the plasma with more IgG1, less IgG2 and more IgG4, indicating a switch to T helper 1 phenotype. Finally, peritumoral B cell infiltration was a positive prognostic sign for overall survival in the 30 HNSCC patients investigated, irrespective of IL-12 treatment. In conclusion, these data indicate that after i.t. IL-12 treatment in HNSCC, significant activation of the B cell and the B cell compartment occurred and that the presence of tumor infiltrating B cells correlated with overall survival of HNSCC patients. ' 2008 Wiley-Liss, Inc.Key words: interleukin-12; B cell; head and neck squamous cell carcinoma; secondary follicles; germinal center Interleukin-12 (IL-12) is a heterodimeric cytokine that consists of 2 disulfide-linked subunits, i.e., IL-12p40 and IL-12p35.1 IL-12 has a wide range of biological activities 1,2 and has effects on both the innate and adaptive immune system. It stimulates the proliferation and activation of cytotoxic T lymphocytes (Tc) and natural killer (NK) cells and induces the production of cytokines, especially IFN-g.3-5 IL-12 is the key cytokine in the induction of T helper 1 (Th1) responses and thereby of cellular immunity. Furthermore, it inhibits angiogenesis. 6 Because of these abilities, IL-12 was used in preclinical models of antitumor immunotherapy. IL-12 induced regression of established primary tumors, inhibited the formation of tumor metastases and prolonged the survival of tumor-bearing mice.7-10 Several phase I 11-16 and phase II studies in various cancer types [17][18][19][20] have been performed, but only a limited number of clinical responses were observed. In most clinical studies, the immunological effects of IL-12 were studied in peripheral blood. However, after IL-12 administration a transient lymphopenia with a redistribution of activated immune cells from the peripheral blood to the lymph nodes (and primary tumor) occurred. 21 Thus, monitoring of the immune effects of IL-12 therapy solely in the peri...

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Interleukin 12: Stumbling Blocks and Stepping Stones to Effective Anti-Tumor Therapy

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Immunotherapeutic Modalities in the Treatment of Head & Neck Squamous Cell Carcinoma

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