Lymphocytes in tumor-draining lymph nodes co-cultured with autologous tumor cells for adoptive cell therapy

Abstract

Background Tumor-draining lymph nodes (TDLNs) are primary sites, where anti-tumor lymphocytes are primed to tumor-specific antigens and play pivotal roles in immune responses against tumors. Although adoptive cell therapy (ACT) using lymphocytes isolated from TDLNs were reported, characterization of immune activity of lymphocytes in TDLNs to tumor cells was not comprehensively performed. Here, we demonstrate TDLNs to have very high potential as cell sources for immunotherapy. Methods Lymphocytes from TDLNs resected during surgical operation were cultured with autologous-tumor cells for 2 weeks and evaluated tumor-reactivity by IFNγ ELISPOT assay. We investigated the commonality of T cell receptor (TCR) clonotypes expanded by the co-culture with tumor cells with those of tumor infiltrating lymphocytes (TILs). Results We found that that TCR clonotypes of PD-1-expressing CD8+ T cells in lymph nodes commonly shared with those of TILs in primary tumors and lymphocytes having tumor-reactivity and TCR clonotypes shared with TILs could be induced from non-metastatic lymph nodes when they were co-cultured with autologous tumor cells. Conclusion Our results imply that tumor-reactive effector T cells were present even in pathologically non-metastatic lymph nodes and could be expanded in vitro in the presence of autologous tumor cells and possibly be applied for ACT.

IL-7R licenses a population of epigenetically poised memory CD8 + T cells with superior antitumor efficacy that are critical for melanoma memory

“…TILs commonly used for adoptive transfer include only a small fraction of tumor-specific cells, also include suppressive T cell populations ( 10 ), largely lack memory/stemness properties ( 12 , 13 ) and commonly express markers of exhaustion, ( 17 , 18 ), limiting their functional antitumor activity. The tumor-draining lymph node is a potential source of T cells with a memory/stemness program that lack exhaustion and has been proposed in other cancer types ( 75 ). Importantly, we show that >95% of tumor-specific CD8 + T cells in the postimmunotherapy tumor-draining lymph node express high levels of IL-7R, which is otherwise sparsely expressed in the lymph node by nonantigen-specific cells.…”

Tumor-draining lymph nodes: opportunities, challenges, and future directions in colorectal cancer immunotherapy

“…39 Adoptive cell therapy (ACT) TDLNs are a good source for ex vivo expansion of immune cells. 40 41 Tumor-reactive T-cells in non-metastatic LNs can be expanded in vitro, 1 indicating their potential for ACT. Lymphocytes in SLNs are the first LNs to receive tumor antigen stimulation and possess potent tumor recognition-specific immune memory and are considered an ideal starting source of cells for ACT.…”

“…Tumor-draining lymph nodes (TDLNs) are located along the lymphatic drainage pathway of primary tumors and are the primary sites at which anti-tumor lymphocytes are activated by tumor-specific antigens. 1 TDLNs contain tumor-specific T cells and are a good source of T cells for colorectal cancer (CRC) immunotherapy. In patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) CRC, extensive lymph node (LN) dissection confers almost no clinical benefit to long-term survival.…”

Harnessing novel strategies and cell types to overcome immune tolerance during adoptive cell therapy in cancer

“…Interestingly, tumor-reactive T cells could similarly be isolated from both metastatic and non-metastatic lymph nodes in which suitable clones can be expanded for ACT therapy. 44 The application of adoptive T cell transfers may not be limited to cytotoxic CD8 T cells. Type 1 T helper cells (Th1) can produce growth factor IL-2 and inflammatory cytokines such as IFNγ, both of which could act to prime the TME for adequate responses by cytotoxic lymphocytes.…”