Lymphocytes infiltrating colorectal cancer have low proliferative capacity but can secrete normal levels of interferon ?

Abstract

Significant numbers of infiltrating mononuclear cells are commonly observed in solid tumours, although their role in restricting tumour growth is not clear. Tumour-infiltrating lymphocytes (TIL) from 38 patients with colorectal cancer, in parallel with peripheral blood lymphocytes (PBL), were assayed to determine their ability to proliferate in response to concanavalin A (ConA), interleukin-2 (IL-2), ConA+IL-2, phorbol 12-myristate 13-acetate (PMA)+ionomycin ionomycin (IOM), and staphylococcal enterotoxin B(SEB). These reagents were selected to give a range of weak to strong proliferative responses either via or independent of the T cell receptor. Proliferation of TIL was significantly lower than that of PBL in all cultures: ConA (P < 0.001), IL-2 (P = 0.002), ConA+IL-2 (P < 0.001), PMA+IOM (P < 0.001), SEB (P = 0.002). In addition to the low proliferative capacity of TIL, production of cytokines by TIL may also play a role in control of tumour growth. We have assayed IFN gamma production in the supernatants from 16 paired TIL and PBL cultures, and tumour necrosis factor alpha (TNF alpha) in 6 paired cultures. TNF alpha concentrations were significantly lower in TIL cultures than in PBL cultures stimulated with ConA (P < 0.05), but no different in control or IL-2 stimulated cultures. IFN gamma levels did not significantly differ between PBL and TIL cultures, indicating that despite the restricted proliferative capacity of TIL, these cells remain capable of secreting significant amounts of IFN gamma.

Comparison of the Effects of Immunosuppressive Factors from Newly Established Colon Carcinoma Cell Cultures on Human Lymphocyte Proliferation and Cytokine Secretion

“…Our findings concerning the production of IL-1ß and TNF-· were somewhat contradictory in that some tumor culture supernatants inhibited their production, while others enhanced it. However, this is in line with the findings of other researchers [1,18].…”

“…For example, it has been demonstrated in vitro that peripheral blood lymphocytes, and in particular tumor-infiltrating lymphocytes from patients with colorectal cancer [1] and other types of tumors [2] proliferate to a lesser extent upon mitogen stimulation than peripheral blood lymphocytes from normal controls. In addition, a stage-dependent, decreased mitogeninduced production of cytokines has been observed in blood cell cultures from tumor patients [3,4].…”

Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation

“…The data presented here suggest that the ability of TIL to secrete cytokines [17,35] and to overexpress activation markers [36,37] in response to polyclonal stimuli differs in cultures at physiological pH e or at the low pH e commonly found in tumor microenvironment. Studies on proliferation and cytotoxic activity in an acidic medium have shown that both NK and LAK cells display impaired cytotoxic activity against tumor cells [38,39], and low levels of cytokine production and metabolic activity [40] in such conditions.…”

“…By contrast, strong anti-tumor responses depend on vigorous activation of effector T cells [13]. Although significant T cell infiltration of the tumor is often observed, these cells have compromised proliferative and effector functions [14][15][16][17][18]. In hypoxic conditions, tumor cells remain viable and are resistant to radiotherapy and chemotherapy [19][20][21], whereas the proliferation of tumor-infiltrating lymphocytes is compromised [22].…”

Interleukin 2 restores CD3-ζ chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases

“…In addition to the local suppression of T cells within the tumour, more general and systemic defects in cell-mediated immunity have been described in cancer patients, including those with colorectal cancer (Nakagomi et al, 1993; 0 Cancer Research Campaign 1998 Bateman et al, 1995;Coventry et al, 1996). The mechanism underlying the immune suppression of the tumour-bearing host is not fully understood but may involve structural defects in the TCR-CD3 complex and its associated signal transduction pathways (Mizoguchi et al, 1992;Finke et al, 1993;Nakagomi et al, 1993).…”