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Therapy Implications for Adoptive Cell Transfer Gastrointestinal Cancers and Melanoma

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Therapy Implications for Adoptive Cell Transfer Gastrointestinal Cancers and Melanoma The Journal of Immunology Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy Simon Turcotte, Alena Gros, Katherine Hogan, Eric Tran, Christian S. Hinrichs, John R. Wunderlich, Mark E. Dudley, and Steven A. Rosenberg Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the pro- portions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 3 109 T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 6 1.4% CD3+CD8+ cells compared with 63 6 2.4% from melanoma (p < 0.001). IFN-g ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells. The Journal of Immunology, 2013, 191: 2217–2225. ancers arising from the gastrointestinal (GI) tract mucosa of common epithelial tumors, such as metastatic GI adenocarci- rank in the 10 most frequent solid malignancies and causes nomas. C of cancer-related death (1). Despite the combined use of Indirect evidence suggests that T cell immunity may participate surgery, chemotherapy, and targeted agents, the great majority of in controlling disease progression for GI adenocarcinomas arising patients with GI adenocarcinomas will die of metastatic disease, in the esophagus, stomach, pancreas, liver, bile ducts, gallbladder, and thus new therapies with curative potential are needed. In the colon, and rectum (10–18). A redefinition of prognostic staging is past few decades, immunotherapy for solid tumors has emerged being proposed based on the density of the TILs found in primary as a promising approach (2–4). Treatment goals for patients with tumors, among which colorectal cancer has been studied most ex- metastatic melanoma are changing, given that the adoptive cell tensively (19). For example, patients with a primary colon cancer transfer (ACT) of autologous tumor-infiltrating lymphocytes (TILs) highly infiltrated by CD3+ TILs appear to have similar disease- can mediate complete and durable cancer regression in patients free survival, irrespective of whether the tumor is confined to the with heavy disease burden, refractory to all other treatments (5). colon (stage I and II) are has spread to draining lymph nodes (stage Cancer centers in and outside the United States have begun to III) (17). Genes involved in cytotoxicity and lysis, such as IFN-g offer this form of immunotherapy and report similar response rates, and granzyme B, appear to be transcribed at lower levels in tumors and multicenter trials are expected (6–9). Although the efficacy of with aggressive features such as microvascular and perineural in- TIL-based ACT may be linked to the more immunogenic nature of vasion compared with tumor with more favorable pathological melanoma compared with other solid cancers, it remains to be features (16). Additionally, active mechanisms employed by colon determined whether this approach can be adapted for the treatment cancer to evade immune recognition have been correlated with lower TIL infiltration and poorer clinical outcomes, such as down- regulation of MHC class I (MHC-I) expression by cancer cells (20), and high levels of immunosuppressive molecules such as IDO1 Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 found in the tumor microenvironment (21). In colorectal cancer metastatic to the liver (stage IV), longer survival of patients after Received for publication February 25, 2013. Accepted for publication June 26, 2013. complete resection of metastases has been associated with a higher This work was supported by the Intramural Research Program of the National In- + + stitutes of Health, National Cancer Institute, Center for Cancer Research. density of CD4 and CD8 TILs in metastases and their relative + Address correspondence and reprint requests to Dr. Steven A. Rosenberg, Surgery abundance compared with FOXP3 T cells (putative regulatory Branch, National Cancer Institute, 10 Center Drive MSC 1201, CRC Room 3-3940, T cells [Tregs]) (22, 23). However, in vitro evidence of MHC- Bethesda, MD 20892. E-mail address: [email protected] restricted recognition of autologous GI cancers by TILs is limited. The online version of this article contains supplemental material. CD4+ TIL clones reactive to a self epitope presented by HLA- Abbreviations used in this article: ACT, adoptive cell transfer; GI, gastrointestinal; DRb1 expressed by an autologous colon cancer cell line derived IHC, immunohistochemistry; MHC-I, MHC class I; REP, rapid expansion protocol; TIL, tumor-infiltrating lymphocyte; Treg, regulatory T cell. from a liver metastasis and transduced to express MHC class II This article is distributed under The American Association of Immunologists, Inc., has been reported (24). More recently, a low frequency of cyto- + Reuse Terms and Conditions for Author Choice articles. toxic CD8 TIL clones were found to specifically recognize newly www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300538 2218 TILs IN GASTROINTESTINAL AND MELANOMA METASTASES established autologous cancer cell lines in three metastatic GI Immunohistochemistry cancer patients, restricted by specific MHC-I molecules (S. Turcotte, Staining of paraffin-embedded tissue was done at the National Cancer A. Gros, E. Tran, C.-C.R. Lee, J.R. Wunderlich, P.F. Robbins, and Institutes Clinical Research Center Pathology Laboratory following stan- S.A. Rosenberg, submitted for publication). dard procedures with appropriate positive and isotype controls. Abs and To test the feasibility of TIL-based ACT for patients with ad- staining conditions were as follows: anti-CD3 (F7.2.38; Dako, Carpinteria, vanced GI cancers, we assessed the phenotype, the proliferative CA, 1:800; PT Link high pH Ag retrieval solution, Dako FLEX+ mouse detection), anti–pan-MHC-I (HC-10, noncommercial Ab, 1:1000, citrate potential, and whether TILs reactive to autologous tumor could be buffer [pH 6.0] Ag retrieval in pressure cooker), anti-HLA-DR (TAL.1B5; identified. These features were evaluated with 14 GI adenocarci- Dako, 1:200, citrate buffer [pH 6.0] Ag retrieval). One pathologist (C.-C.R. nomas metastatic to the liver and the lungs that were harvested in Lee) reviewed all slides and performed semiquantitation for MHC expres- patients refractory to standard chemotherapy. To put these findings sion and lymphocyte counts in tumoral and peritumoral tissues. in perspective, we compared these GI TIL immune features with Flow cytometry TILs derived from 42 contemporaneous melanoma metastases also Analyses of PBMCs and cell suspensions derived from metastases and ad- harvested from the liver and the lungs. jacent normal tissues were performed after overnight incubation in complete media without IL-2 at 37˚C in humidified atmosphere of 5% CO2. The fol- lowing mAbs specific for human Ags and appropriate isotype controls were Materials and Methods used: from BD Biosciences, allophycocyanin-H7–conjugated anti-CD3 Patients, PBMCs, and tumor and normal samples (SK7), PE anti-CD25 (2A3), Alexa Fluor 700 anti-CD27 (M-T271), FITC anti-CD28 (CD28.2), PE/Cy7 anti-CD45RO (UCHL1), allophycocyanin anti- Patients with metastatic GI cancer (n = 14) and melanoma (n =42)un- derwent liver and lung metastases resections between December 2007 and CD62L (Dreg 56), FITC anti–CD134/OX-40 (ACT35), allophycocyanin anti– March 2012 after giving their written informed consent under protocols CD137/4-1BB (4B4-1), allophycocyanin anti–PD-1 (MIH4); from Invitrogen: approved by the Institutional Review Board of the National Cancer Insti- R-PE-Texas Red–conjugated anti-CD8 (3B5); and from eBioscience, allo- tute (see Supplemental Tables I and II for patient clinicopathological phycocyanin anti-FOXP3 (236A/E7). Cells were resuspended in staining buffer (PBS containing 3% FBS) and blocked with mouse IgG mAbs (Caltag characteristics). At least 4 wk had to have elapsed after the last dose of Laboratories, Burlingame, CA) for 15–30 min at room temperature. Cells systemic chemotherapy prior to metastasectomy. PBMCs were obtained from patients with GI cancer on the morning of their surgery after veni- were stained with mAb against surface Ags for 30 min at 4˚C in the dark. For puncture (sodium-heparin glass tubes, BD Vacutainer; BD Biosciences, intracellular FOXP3 staining, cells were processed with the eBioscience stain- San Jose, CA) and prepared over Ficoll-Hypaque (LSM gradient, ICN ing buffer set. Acquisition of at least 20,000 events was done on FACSCanto Biomedicals, Aurora, OH) gradient. Freshly resected tumors were sent II flow cytometer (BD Biosciences). Cell aggregates and dead cells were from the surgery suite to the laboratory in sterile containers with saline and excluded by forward and side scatter, and with propidium iodide staining for unfixed cells. Flow cytometry analysis was carried out with FlowJo v7.5.5 on ice. Under sterile conditions, tumors were dissected away from adjacent software (Tree Star, Ashland, OR), gating based on isotype control Ab normal tissue and stroma.
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