Tumor-infiltrating lymphocytes and Associations with cancer treatments
Tumor-infiltrating lymphocytes are white blood cells that have left the bloodstream and migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ which consist of both mononuclear and polymorphonuclear immune cells, (i.e., T cells, B cells, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, basophils, etc.) in variable proportions. Their abundance varies with tumor type and stage and in some cases relates to disease prognosis.
TILs can often be found in the tumor stroma and within the tumor itself. Their functions can dynamically change throughout tumor progression and in response to anticancer therapy.
TILs are implicated in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes (after surgery or immunotherapy)
Detection and characteristics
TILs can be found between the tumor cells, as TILs in the stroma surrounding the tumor cells do not count. TILs are often found floating around the tumor without actual penetration or action on the tumor cells. Histologic definitions for TILs vary.
CD3 has been used to detect lymphocytes in tumor samples. Tumor immune infiltration can also be determined using gene expression methods like Microarray or RNA Sequencing through deconvolution methods such as CIBERSORT. Such methods allow for systematic TIL enumeration and characterization of the tumor microenvironment in diverse cancer types and across thousands of tumors, an approach largely led by Ash Alizadeh, Ajit Johnson among others. Detection of gene expression specific for different kind of immune cell populations can then be used to determine the degree of lymphocyte infiltration as has been shown in breast cancer. An active immune environment within the tumor often indicates a better prognosis as can be determined by the Immunological constant of rejection.
Use in autologous cell therapy
They are key to an experimental autologous cell therapy (Contego) for metastatic melanoma. Autologous TIL therapy for metastatic melanoma has broad T cell recognition of both defined and undefined tumor antigens against all human leukocyte antigen (HLA) restrictions. TILs can not only recognize over-expressed self/melanocyte differentiation antigens, such as Melan-A/MART-1 (melanoma-specific), gp100, tyrosinase, and survivin, but TILs can also recognize other unknown antigens specific to the tumor and individual patient.
Clinical Success
The combination of TILs with a high dose of IL-2 presents multiple clinical trials demonstrating rates near 50% or more patients effectively responding. In summary of TIL therapy clinical trials, TIL therapy was found to induce complete and durable regression of metastatic melanoma. Tumor reduction of 50% or more was observed in about half of patients. Some patients experienced complete responses with no detectable tumor remaining years after treatment. In one clinical trials, among the 93 patients treated with TILs, 19 patients had complete remissions that lasted greater than 3 years.
Clinical trials using TILs to treat digestive tract cancers, such as colorectal cancer, and cancers associated with the human papilloma virus (HPV), such as cervical cancer, are ongoing. In colorectal cancer, TILs are associated with microsatellite instability cancers, as may be seen in Lynch syndrome. Also, TILs are associated with most effective immune checkpoint inhibitor therapy in GI cancers. They are an important prognostic factor in melanoma and higher levels being associated with a better outcome. TILs are also associated with better outcomes in epithelial ovarian cancer.
The use of TILs to treat other tumor types, including lung, ovarian, bladder, and breast, are under investigation.
Associations with cancer treatments
TIL therapy in combination with prior immunotherapy treatment, such as IL-2 and anti-CTLA4 (ipilimumab) had higher response rates and more durable responses in clinical trials. This suggests a synergistic effect of prior immunotherapy with TIL therapy. Current studies involve investigating the roles of chemotherapy drugs in combination with TIL therapy to assess improved response rates and synergistic efficacy.
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