Naïve CD8(+) T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment.
Despite of the potential implications for cancer immunotherapy, conventional approaches using in vitro expanded CD8(+) T cells have suboptimal outcomes, mostly due to loss of functionality from cellular exhaustion. We therefore investigated the phenotypic and functional differences among in vitro activated CD8(+) T cells of three different sources, namely naïve (NTeff), memory (MTeff) and tumor-infiltrating lymphocytes (TILeff) from human and mice, to better understand mechanisms behind potent effector functions and potential for overcoming current limitations. In line with the greater proliferation activity and longer telomere lengths of NTeff populations, cells of naïve origin exhibited significantly less amounts of T cell exhaustion markers than those of MTeff and TILeff, and moreover, acquired distinct expression patterns of memory-promoting transcription factors, T-bet and Eomes, induced in a rapid and sustainable manner. NTeff cells appeared to have lower expression of Foxp1 and were refractory to apoptosis upon TGF-β conditioning, implying better survival potential and resistance to tumor-induced immune suppression. Of CD8(+) T cell pools activated to tumor-specific CTLs, naïve cell generated effectors possessed the most potent cytotoxic activity, validating implications for use in rational design of adoptive immunotherapy.
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Hong Hanh
HH
Nguyen
Department of Medical Sciences, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Therasa
T
Kim
Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Sang Yun
SY
Song
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Somang
S
Park
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Hyang Hee
HH
Cho
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Sung-Hoon
SH
Jung
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Jae-Sook
JS
Ahn
Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Hyeoung-Joon
HJ
Kim
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Je-Jung
JJ
Lee
Academy of Immunology &Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Republic of Korea.
Hee-Ok
HO
Kim
Academy of Immunology &Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Republic of Korea.
Jae-Ho
JH
Cho
Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.
Deok-Hwan
DH
Yang
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D012097:Repressor Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D016212:Transforming Growth Factor beta / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta