Phenotype and Function of T Cells Infiltrating Visceral Metastases from Gastrointestinal Cancers and Melanoma: Implications for Adoptive Cell Transfer Therapy

Abstract

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 proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 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 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ 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.

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

“…Therefore, TNF-neutralizing molecules might be useful in nonimmunocompromized patients affected with immunogenic melanoma. Interestingly, HLA-I expression was detected on more than 50% of melanoma cells in 69% of melanoma metastases (49). Evaluating HLA-I expression in melanoma biopsies would help define eligibility of patients for TNF blockade treatment.…”

Advances and Prospects in Cancer Immunotherapy

“…There are reports indicating that antitumor activity was detected in TIL samples of 81% of patients with metastatic melanoma [151], which was one of the best situations for generating tumor-reactive TILs. From patients with gastrointestinal (GI) cancers, however, less than 3% of expanded bulk TILs were tumor-reactive [162]. Thus, there is need to employ genetic methods to modify T cells to increase antitumor activities for adoptive cell therapy of cancer patients.…”

“…Thus, adoptive cell transfer therapy with antitumor TILs may be extended to treat patients with other forms of cancers such as breast, renal, and lung cancers. Recent studies have shown that TILs generated from liver and lung metastases from patients with GI cancers had similar proportions of CD8 + T cells, T cell differentiation stage, expression of costimulatory molecules, and expansion scale for clinical application to those derived from patients with metastatic melanoma [162]. Different from TILs from metastatic melanoma, however, TILs from GI cancers usually did not maintain the antitumor activity after large-scale expansion and less than 3% of expanded bulk TILs from GI cancers were tumor-reactive.…”

“…Thus, the obstacle for adoptive transfer therapy with TILs for patients with GI cancers was the loss of the antitumor reactivity of TILs after expansion. Use of selected and enriched tumorreactive T cells instead of bulk TILs for expansion may keep the antitumor reactivity of expanded TILs [162]. It is expected that adoptive cell therapy with antitumor TILs can be successfully used in the treatment of patients with various forms of cancers.…”

A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells

“…Studies have demonstrated that 4-1BB expression on tumor-infiltrating lymphocytes (TIL) can be used to identify tumor-reactive T cells (13,14), leading to the use of 4-1BB-selected TILs for adoptive cell therapy in a clinical trial for metastatic melanoma patients (NCT02111863). With regards to activation of the 4-1BB pathway, several preclinical studies have reported increased antitumor responses following treatment with an agonistic a-4-1BB mAb, primarily via CD8 þ T-cell activation (15)(16)(17).…”