The Different Functional Distribution of “Not Effector” T Cells (Treg/Tnull) in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide, ranking as high as the second leading cause of cancer-related deaths in industrialized countries. Consistent with immunosurveillance theory, the immune system is crucial to protect the host from developing tumors, and the major players in tumoral immunity are effector T cells. Anyway, cancer cells develop strategies of immunoevasion influencing the cancer-specific lymphocyte priming, activation, and effector function. Therefore, the T cell subsets that mature during the stages of tumor growth, differently contribute to disease progression and/or regression. In our study, we analyzed the intra-tumoral and peripheral T cell subsets’ distribution in 30 patients with CRC, in order to clarify their functional role toward cancer. We found that percentage of infiltrating effector T cells decreased in cancer tissue than in healthy mucosa and that the tumor microenvironment negatively influences the cytolytic activity of T lymphocytes reactive to cancer cells. Moreover, we found that the tumor tissue was infiltrated by a large amount of “not effector” T (neT) cells with a regulatory or an anergic profile, which are unable to kill cancer cells, may be contributing to the CRC promotion. The presence of neT cells was investigated also in the peripheral blood of CRC patients, demonstrating that the peripheral T regulatory cells can inhibit the proliferation of effector T cells, confirming their immunosuppressive properties. Finally, monitoring the changes in circulating neT cells’ frequencies after the tumor removal, we confirmed the role of cancer in the modulation of immune system, in particular, in supporting a Tregs-mediated immunosuppression.

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

“…In particular, we have chosen IFN-γ, IL-17A, 344 IL-8, IL-1β, IL-1α, IP-10, MIP-1α and IL-9. The results of the BVS Dirichlet Multinomial Regression 345 (step 2) are reported in Table 4 and Table 5 with our previous findings, where we documented the weakening of the effector functions of T cell 364 clones isolated from adjacent healthy mucosa compared to the cancerous one and the increase of T 365 lymphocytes' subsets (Th2/Th0/Tregs/Tnull) that can promote tumor progression 9 . Contextually, the 366 Th2 harmful role in tumor development has been well established; a Th2 shift in the tumor 367 microenvironment, especially for CRC, strongly contributes to cancer relapse, metastasis, and worse are contradictory, excess inflammation caused by CD4 + and CD8 + IL-17 producing T cells or the 370 immunosuppression induced by Treg may lead to carcinogenesis 43 44 .…”

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

“…Colorectal tumors may evade the immune response through multiple mechanisms, including upregulation of the expression of immune inhibitory molecules, leading to T‐cell anergy . In addition, several dysfunctional T cells lacking cytotoxic effects are suppressed by the tumor milieu . Suppression may involve regulatory T cells (Tregs) that secrete immunosuppressive cytokines, as well as myeloid and stromal cells that modulate immune checkpoints through the activation of co‐inhibitory molecules on T cells …”

“…The failure of treatment efficacy has been attributed to the heterogeneity of the immune cell constitution and unknown T‐cell phenotypes and status of different tumors . Therefore, studies have been directed to elucidate the mechanisms underlying T‐cell function and distribution in tumor lesions for the identification of appropriate strategies to boost antitumor T‐cell response . Very little is known about the diversity of T‐cell compartments at the tumor site of CRC.…”

“…7 In addition, several dysfunctional T cells lacking cytotoxic effects are suppressed by the tumor milieu. 11 Suppression may involve regulatory T cells (Tregs) that secrete immunosuppressive cytokines, as well as myeloid and stromal cells that modulate immune checkpoints through the activation of co-inhibitory molecules on T cells. 12 Current checkpoint blockade therapies are desired to rescue T cells from exhaustion or deplete Tregs, and may not be efficient in treating microsatellite stable (MSS) CRCs.…”

“…13 Therefore, studies have been directed to elucidate the mechanisms underlying T-cell function and distribution in tumor lesions for the identification of appropriate strategies to boost antitumor T-cell response. 11,14,15 Very little is known about the diversity of T-cell compartments at the tumor site of CRC. Our knowledge about T-cell diversification is not systematic and comprehensive but is based on specific markers 16 ; there is a definite lack of the elusive definition of cell type and dynamics.…”