In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers

Abstract

Mononuclear cells infiltrating human brain tumors were isolated from seven of nine surgical biopsy specimens. These cells were small T11+, T3+ lymphocytes that did not express DR antigens or the receptor for interleukin-2. In addition, large granular lymphocytes were recovered from two of these tumors. The clonogenic potential of tumor-infiltrating lymphocytes (TIL's) was assessed by limiting-dilution analysis (LDA) using a microculture system that permits proliferation of virtually 100% of normal peripheral blood T lymphocytes (PBL-T's). In comparison to normal and autologous PBL-T's, TIL's had a strikingly reduced proliferative potential revealed by a decrease in the frequency of proliferating T lymphocyte precursors calculated by LDA. On average, only one of every 100 T cells from TIL's was able to proliferate, as compared to one of every two or all of the T cells from the patient's peripheral blood or from normal donors. Furthermore, the TIL populations showed depressed proliferative responses to the lectins phytohemagglutinin and concanavalin A and to the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate. Clonal analysis performed on the proliferating microcultures from three tumors demonstrated that the majority of these clones possessed cytolytic activity against various tumor cell targets. Among clones tested for cytolytic activities with glioma cells, four lysed cultured autologous tumor cells, and the specific lysis was greater than 50% in all cases. Numerous clones with natural killer (NK)-like activity were obtained from two TIL preparations, and the frequency of cytolytic T lymphocyte precursors with NK-like activity was determined for one of these preparations and was found to be higher than that in the patient's peripheral blood. Glioma cells grown in culture and then mixed with normal peripheral blood lymphocytes (PBL's) were capable of inhibiting the PBL's response to lectins. This inhibitory property may account in part for the observed poor clonogenicity of TIL's from brain tumors. Nevertheless, nearly all proliferating clones displayed cytotoxicity against either autologous or allogeneic tumor cell targets and may imply selective accumulation of cytolytic effector cells at the tumor site.

Tumor-infiltrating lymphocytes (TILs) from patients with glioma

“…27 In concert with IL-21, IL-15 has been shown to overcome immunosuppressive effects on tumor-reactive T cells, in part by neutralizing negative effects of tumor-associated macrophages 28 and by increasing antitumor activity in CD8 C T cells. 29 IL-2, IL-15 and IL-21-expanded TILs from glioma lesions could be used for cellular therapy with the hope to achieve clinically relevant responses as it has been reported for patients with melanoma or other solid cancers.…”

Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

“…Immune suppression mediated by TGF-b appears to be due to impairment of IL-2R function and suppression of high affinity IL-2R expression, 29 inhibition of natural killer cells (NK) and lymphokine-activated killer cells (LAK) induction and proliferation, 30,31 and the inhibition of maturation and antigen presentation of dendritic cells. 32,33 However, effector cells, once they become activated, are refractory to the immune inhibitory properties of TGF-b and are capable of targeting and destroying tumor cells that continue to secrete TGF-b.…”

Predominance of a type 2 intratumoural immune response in fresh tumour-infiltrating lymphocytes from human gliomas

“…For instance, the production of TGF-by gliomas has been reported to suppress T cell antitumoural activity [43]. Accordingly, little or no cytotoxicity has been observed in fresh glioma TIL, but is reportedly inducible in vitro in TIL cultured with IL-2 for a few days, where selective expansion of Th1 type clones might occur [3,44]. Another study done on expression of cytokines in skin tumours found that IL-4, IL-10, and GM-CSF were predominantly expressed in the RNA isolated from mass of progressive epidermal neoplasias [45].…”

“…In human gliomas, data on characterization of fresh tumour-infiltrating lymphocytes (TIL) are limited. Glioma TIL are known to be predominantly T cells [2,3], but little is known about their intratumoural state of activation. Activation with increased cell adhesion molecule expression is necessary for leucocytes to infiltrate tissues and adhere to the targeted tumour cells [4][5][6].…”