MHC class‐I‐restricted auto‐tumor‐specific CD4⁺CD8 ⁻T‐cell clones established from autologous mixed lymphocyte‐tumor‐cell culture (MLTC)

Abstract

Autologous mixed lymphocyte-tumor cell cultures (MLTC) were initiated with cytokine (IFN gamma and TNF alpha)-treated ex-vivo tumor cells of lung, ovarian, breast and stomach carcinomas. The cytokine-treated tumors expressed class-I but not class-II molecules. Although the proportion of CD8+ lymphocytes increased in the bulk culture of MLTCs, in 5/7 experiments the majority of the established T-cell clones were CD4+. Among the CD8+ clones a high proportion (77%) was cytotoxic, while the proliferative response was more frequent among the CD4+ clones (70%). In 4/26 cytotoxic T-lymphocyte (CTL) clones (3/17 CD4+ and 1/9 CD8+), derived from a patient with class I+ class II- stomach carcinoma, lysis was restricted to the autologous tumor cells. These auto-tumor-specific clones did not lyse the autologous ConA blasts, the 5 allogeneic ex-vivo tumors, the NK-sensitive K562 or the relatively sensitive Daudi cells. The cytotoxicity of these clones was inhibited by pre-incubation of the tumor cells with W6/32 (alpha-class I) MAb, or by preincubation of the lymphocytes with OKT3 (alpha-CD3) MAb. The alpha-CD4 (OKT4) MAb had only a marginal effect on the CD4+ clones, while the lytic function of the CD8+ clone was inhibited by the alpha-CD8 (OKT8) MAb. The 3 CD4+ CTL clones also responded with proliferation to the autologous tumor cells. This proliferative response was inhibited by the presence of W6/32 MAb. Our results indicate that the auto-tumor lysis exerted by CD4+ CTL clones was restricted by the class-I antigens, and that the CD4 molecules of the clones were not essential for the lytic interaction.

Cytotoxic T‐cell clone against rectal carcinoma induced by stimulation of a patient's peripheral blood mononuclear cells with autologous cultured tumor cells

“…Other investigators (Fleischer et al, 1986;Hayashi et al, 1992;Itoh et al, 1992;Kharkevitch et al, 1994;LeMay et al, 1993;Morisaki et al, 1994;Strassman and Bach, 1984;Wang et al, 1992) have also described CD4 1 HLA class I-dependent CTLs. However, in several of those studies (Hayashi et al, 1992;Kharkevitch et al, 1994;LeMay et al, 1993;Morisaki et al, 1994), target cell lysis by the CD4 1 CTLs was weak (requiring overnight incubation of CTL with targets), whereas the CD4 1 CTLs described here rapidly (4-6 hr) and effectively lysed (up to 80% lysis) autologous tumor cells.…”

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

“…Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). Our laboratory has developed PDOX models of all major tumor types including pancreatic [15–19], breast [20], ovarian [21], lung [22], cervical [23], colon [24–26] and stomach cancer [27] as well as mesothelioma [28] and sarcoma [6 29–31]. …”

Longitudinal Assessment of Lung Cancer Progression in Mice Using the Sodium Iodide Symporter Reporter Gene and SPECT/CT Imaging

“…However, PDX solid tumors, when grown s.c. in immunocompromised mice, do not metastasize [46]. Similar to the research described here, patient-derived orthotopic xenograft (PDOX) can lead to metastasis when implanted orthotopically in mouse models and thus are able to better recapitulate human tumors [47]. Since orthotopic mouse models necessitate non-invasive imaging to follow disease progression and response to therapy, future studies should establish genetically modified PDOX mouse models that could be imaged using small animal SPECT/CT and other imaging modalities.…”