title: Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer Are Marked by Expression of IL7 Receptor and c-myc.
abstract: The optimal T-cell attributes for adoptive cancer immunotherapy are unclear. Recent clinical trials of ex vivo-expanded tumor-infiltrating lymphocytes indicated that differentiated T effector cells can elicit durable antitumor responses in some patients with cancer, with their antitumor activity tightly correlated with their persistence in the host. Thus, there is great interest in the definition of intrinsic biomarkers that can predict the conversion of short-lived tumor antigen-specific T effector cells into long-lived T memory cells. Long-term persistence of ex vivo-expanded tumor-specific CD8+ T effector clones has been reported in refractory metastatic melanoma patients after adoptive T-cell transfer. By using highly homogeneous clone populations from these preparations, we performed a comparative transcriptional profiling to define preinfusion molecular attributes that can be ascribed to an effector-to-memory transition. Through this route, we discovered that preinfusion T-cell clones that expressed the IL7 receptor (IL7R) and c-myc were more likely to persist longer after adoptive transfer to patients. The predictive value of these two biomarkers was strengthened by using IL7R protein, IL7-induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor-specific T effector clones capable of engraftment into immunodeficient mice. Overall, our findings reveal IL7R and c-myc expression as intrinsic biomarkers that can predict the fate of CD8+ T effector cells after adoptive transfer.
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Smita S
authors.initials: SS
authors.lastname: Chandran
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Biman C
authors.initials: BC
authors.lastname: Paria
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Rothermel
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stephens
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. udai_kammula@nih.gov.
authors.forename: Udai S
authors.initials: US
authors.lastname: Kammula
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000328:Adult; D000368:Aged; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D020395:Receptors, Interleukin-7