Why do tumor-infiltrating lymphocytes have variable efficacy in the treatment of solid tumors?

Abstract

Lymphocytes in tumor tissue are called tumor-infiltrating lymphocytes (TILs), and they play a key role in the control and treatment of tumor diseases. Since the discovery in 1987 that cultured TILs can kill tumor cells more than 100 times more effectively than T-cells cultured from peripheral blood in melanoma, it has been confirmed that cultured TILs can successfully cure clinical patients with melanoma. Since 1989, after we investigated TIL isolation performance from solid tumors, we modified some procedures to increase efficacy, and thus successfully established new TIL isolation and culture methods in 1994. Moreover, our laboratory and clinicians using our cultured TILs have published more than 30 papers. To improve the efficacy of TILs, we have been carrying out studies of TIL efficacy to treat solid tumor diseases for approximately 30 years. The three main questions of TIL study have been “How do TILs remain silent in solid tumor tissue?”, “How do TILs attack homologous and heterologous antigens from tumor cells of solid tumors?”, and “How do TILs infiltrate solid tumor tissue from a distance into tumor sites to kill tumor cells?”. Research on these three issues has increasingly answered these questions. In this review I summarize the main issues surrounding TILs in treating solid tumors. This review aims to study the killing function of TILs from solid tumor tissues, thereby ultimately introducing the optimal strategy for patients suffering from solid tumors through personalized immunotherapy in the near future.

Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes

“…Surprisingly, the TLS role on surrounding tumor stroma blood vessels was completely neglected, with the TLS interrelation to blood vessels being limited to the high endothelial vessel assessment as part of the criteria used to identify TLSs microscopically [ 57 , 58 ]. Diffuse inflammatory cell infiltration (currently defined as TIL) into malignant tissue stroma induced a high angiogenic response, which is responsible for an increased tumor stroma blood vessel density associated with a high rate of lymphovascular invasion and metastases [ 58 , 59 , 60 , 61 ]. Our search on PubMed and other databases did not help us to find any information related to interactions between TLSs, immature and mature stromal blood vessels, or tumor angiogenesis for any BC molecular subtype.…”

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

“…This immunosuppressive TME has a cellular composition that forms a cellular network in which regulatory and support cells control access, modulate activation, and suppress activity of immune cells, specifically cytolytic T cells and tumor infiltrating lymphocytes (TILs) that are tasked with eradicating tumor cells. 22 Initially classical immunohistochemistry and more recently advanced methods like spatial transcriptomics are contributing to the representative image of solid tumors [23][24][25] with macrophages sometimes occupying more than 50%. 26 Elevated PD-L1 levels have been consistently observed in various immunosuppressive cells within the TME, including TAMs, MDSCs, and even Tregs, which makes PD-L1 a viable therapeutic target for these immunosuppressive cells.…”

Immune checkpoint ligands expressed on mature high endothelial venules predict poor prognosis of NSCLC: have a relationship with CD8+ T lymphocytes infiltration

“…However, the efficacy of immunotherapy varies, and only specific subsets of patients benefit (3). Immune cell recruitment into the tumor microenvironment (TME) may be a critical factor in antitumor immunity and influence the clinical response and prognoses of cancer patients (4)(5)(6). Thus, obtaining an in-depth understanding of the immune infiltrates would be helpful in increasing clinical response and creating new therapeutic strategies for cancer prevention and treatment.…”