Abstract
Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.
Highlights
Cancer immunotherapies, including recombinant cytokines, immune checkpoint inhibitors (ICIs), adoptive T cell therapies, and vaccines, have revolutionized the treatment of Cancer Immunology, Immunotherapy (2020) 69:1989–1999 several solid tumors and hematologic malignancies [1]
The panel of genes consisted of well-known inhibitory immune checkpoints (ICs), PD-1, TIM-3, CTLA-4, V-domain Ig suppressor of T cell activation (VISTA), lymphocyte-activation gene 3 (LAG-3), TIGIT, CD244, CD160, and KLRG1 [24], in addition to T cell exhaustion-related markers namely Thymocyte selection-associated high-mobility-group box (TOX), TOX2, TOX3, TOX4 [9, 14], Helios, PRDM1 (Blimp1), Ki-67 [25], and other markers involved in tumorigenesis such as silent information regulator 1 (SIRT1) [15]
We found that mRNA levels of PD-1, TIM-3, cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), TIGIT, CD160, CD244, and KLRG1 were significantly higher in tumor tissue (TT), compared to normal tissue (NT) (Fig. 1a)
Summary
Cancer immunotherapies, including recombinant cytokines, immune checkpoint inhibitors (ICIs), adoptive T cell therapies, and vaccines, have revolutionized the treatment of Cancer Immunology, Immunotherapy (2020) 69:1989–1999 several solid tumors and hematologic malignancies [1]. They acquire genetic and epigenetic alterations giving rise to new cancer clones with different molecular profiles and inheritable traits favoring tumor growth/survival and immune response escape [5] These alterations can influence the expression of immune checkpoints (ICs), some of which might lead to T cell exhaustion [6, 7]. Thymocyte selection-associated high-mobility-group box (TOX) family members and B lymphocyte-induced maturation protein-1 (Blimp1) are transcription factors, which can indirectly lead to immune evasion and impaired T cell activation by altering cell differentiation and gene expression [9, 13, 14] Other markers, such as SIRT1, Ki-67 and Helios, can influence T cell function and induce immune evasion via indirect mechanisms, and have been implicated in cancer progression [15,16,17,18]. Little is known about the contribution of some of these markers to CRC progression and metastasis, and how their expressions differ during early and advanced stages of the disease
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