Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy
Soft Tissue Sarcomas are a rare and heterogeneous group of tumors, which have a characteristic complexity, leading to a difficult diagnosis and a lack of response to treatment. Based on a nice review, we introduce here the role of immune cells, soluble plasmatic factors, immune checkpoints; and the expression of immune-related genes predicting survival, response to therapy, and potential immunotherapeutic agents or targets in Soft Tissue Sarcomas.
Immune Cell Status in Soft Tissue Sarcoma
Soft Tissue Sarcomas (STS) are a heterogeneous group of diseases of mesenchymal origin. STS represent approximately 1% of solid tumors. This group comprises over 50 different histologic subtypes that affect patients of all ages.For localized STS, surgical resection is the standard treatment. Unfortunately, STS recurs frequently as a locally inoperable or metastatic disease. For a locally advanced or metastatic disease, the usual treatment is chemotherapy. Despite the remarkable improvement in cancer diagnosis and treatment, many patients do not respond to therapy. This limited effectiveness of current strategies is often attributed to the complexity of the disease. That is, at least partly, supported by the complex microenvironment where the tumor is growing and defeating the immune system.
There is a growing interest in studying the immunological status of STS patients. The tumor microenvironment (TME) includes different populations of non-tumor cells, such as endothelial, stromal, cancer-associated fibroblasts and adipocytes, and immune cells.
T cell is a type of white blood cell. T cells are part of the immune system and develop from stem cells in the bone marrow. They help protect the body from infection and may help fight cancer. Also called T lymphocyte and thymocyte. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the immune response.
One of these functions is immune-mediated cell death, and it is carried out by two major subtypes T effector cells: CD8+ "killer" and CD4+ "helper" T cells. (These are named for the presence of the cell surface proteins CD8 or CD4.) CD8+ T cells, also known as "killer T cells", are cytotoxic – this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8+ T cells are also able to use small signaling proteins, known as cytokines, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4+ T cells, function as "helper cells". Unlike CD8+ killer T cells, the CD4+ helper T (TH) cells function by further activating memory B cells and cytotoxic T cells, which leads to a larger immune response.
Regulatory T cells are yet another distinct population of T cells that provide the critical mechanism of tolerance, whereby immune cells are able to distinguish invading cells from "self". This prevents immune cells from inappropriately reacting against one's own cells, known as an "autoimmune" response. For this reason, these regulatory T cells have also been called "suppressor" T cells. These same regulatory T cells can also be co-opted by cancer cells to prevent the recognition of, and an immune response against, tumor cells.
T cells in STS
As all T cells express CD3E protein at their membrane, two studies analyzed the expression profile of CD3E, to explore the level of T cell infiltration in STS. The former suggested that T-cell infiltration could depend on the STS subtype and proposed that a highly mutated tumor type may have greater immunogenicity and a robust T-cell infiltrate. In the latter, CD3E was highly expressed in some STS samples, such as rhabdomyosarcoma and alveolar soft part sarcoma, corroborating the idea that T-cell infiltration depends on the STS subtype.
CD8 and CD4 T cells
CD8 T cells can mediate the lysis of neoplastic cells. For that reason, these cells are usually associated with a direct anti-tumor immune response. Furthermore, there is an influence of these cells on the clinical course of several types of tumors. However, the excessive and constant exposure of CD8 T cells to cancer antigens and inflammatory signals leads to a progressive loss of the T cell effector function; this is called “exhaustion”. Exhausted T cells can be characterized by the presence of inhibitory receptors; PD-1 and LAG3 are among them. The analysis of CD8 T cells in the TME, including their receptor repertoire, has been increasing, given the availability of new activating drugs.
CD4 T cells are also required for anti-tumor immunity. They comprise diverse subsets with different and sometimes opposing roles in TME, upregulating or downregulating the immune response. Regarding their anti-tumor activity, they are responsible for enhancing the cytotoxic function of CD8 T cells, increasing clonal expansion, functioning as antigen-presenting cells, for example. Fresh tumors resected at surgery analyzed have shown a greater prevalence of CD4 than CD8 T cells in well differentiated and dedifferentiated retroperitoneal liposarcoma. The majority of tumor-infiltrating lymphocytes were CD4 ‘helper’ T cells, and most CD8 T cells expressed their programmed cell death protein 1 (PD-1). This information suggests that CD8 T cells have been triggered by tumor antigen but are suppressed. Several studies have been trying to correlate the frequency of immune cells with the prognosis in STS. An association between CD8 T cells and improved outcomes has been observed. However, conflicting studies have also observed an association with poor outcomes. Moreover, there are also other studies that state that there is no statistical significance in this correlation. Concerning CD4 T cells, the controversy remains. Although in some studies, CD4 T cells have been associated with a positive outcome, the opposite, an association with a poor prognosis, has also been observed.
Regulatory T cells
Regulatory T cells (Tregs) are physiologically suppressive cells and play an important role in maintaining the homeostasis of the immune response. They can produce immunosuppressive cytokines such as interleukin 10 (IL-10) and tumor growth factor-β (TGF-β), they can express negative costimulatory molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), PD-1, or PD-L1, and they consume cytokine interleukin 2 (IL-2). These functions lead to an inhibition of T lymphocytes and the promotion of immune escape. Studies of other tumors have associated high density of tumor-infiltrating Tregs with a poor outcome. However, the opposite has also been demonstrated. In STS, D’Angelo et al., observed a high density of tumor-infiltrating Tregs in 75% of STS patients. Later, another study evaluated tumor-infiltrating Tregs and showed an association between the increased infiltration of these cells and a poor prognosis in STS. However, an association has also been found between a greater percentage of Tregs and a better outcome, or a better response to pembrolizumab, anti-PD-1 monotherapy. Due to these controversial results and the limited number of studies, the prognostic significance of Tregs remains undefined.
B cells is a type of white blood cell that makes antibodies. B cells are part of the immune system and develop from stem cells in the bone marrow. Also called B lymphocyte. Recent data have shown that B cells can shape immune responses in tumors. However, the association of these cells with disease prognosis has been a reason for disagreement. In several tumors, it described an association with a good prognosis. However, the opposite has been reported, too. Accumulated more and more data suggest the potential of B cells as biomarkers.
Tumor-infiltrating lymphocytes (TILs) are strong indicators of tumor immunogenicity. TILs have been described in various malignant tumors, including STS, and some studies support the influence of TILs on the progression of some tumors. It was observed that most STS patients had low TIL infiltration. However, in STS, TILs have been only reported considering a few STS subtypes in limited sample size studies. For these reasons, although the presence of TILs and their impact on positive outcomes have been demonstrated in several sarcoma subtypes, these reports may not be representative of all STS.
Dendritic cells (DCs) are antigen-presenting cells (also known as accessory cells) of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems, play an essential role in the immunological environment. A correlation between the presence of tumor-infiltrating DCs and improved disease-specific survival (DSS) in undifferentiated pleomorphic sarcomas (UPS) and myxofibrosarcoma was observed. Although there is a lack of studies concerning DCs in STS, this conclusion suggests an important role of antigen presentation in immune responses against these tumors.
Macrophage is a type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. Macrophages are vital innate immune cells present in tissues, and it has been suggested that they play a role in tumor development and progression. They are differentiated by the local microenvironment into M1 or M2 macrophages, developing a pro- inflammatory (anti-tumor) response or anti-inflammatory (pro-tumor) response, respectively. Macrophages that are differentiated by the TME are called tumor-associated macrophages (TAMs). Due to several factors, for example, IL-4 and IL-13, an M2-like differentiation occurs in the TME, which facilitates tumor immune escape and metastasis. M2-like TAMs block CD8 T cell-mediated anti-tumor immune response either directly, or mediated recruitment of regulatory T cells (Tregs). M2-like TAMs were observed to be associated with worse survival rates for several subtype of STS, confirming the negative prognostic value of TAMs.
Myeloid-Derived Suppressor Cells
Myeloid-derived suppressor cells (MDSCs) are another subset of suppressive cells that can facilitate tumor immune escape, impairing the function of T cells, NK cells, and DCs. These immature myeloid cells can be phenotypically divided into early-MDSCs (e-MDSCs), monocytic MDSCs (M-MDSCs), and polymorphonuclear MDSCs (PMN-MDSCs).
In mice bearing rhabdomyosarcoma, an expansion of MDSCs, preferentially PMN-MDSCs, was observed at the tumor site. It was demonstrated that PMN-MDSCs have an essential role in rhabdomyosarcoma immune escape. Preventing the trafficking of these cells to the tumor could also improve the efficacy of checkpoint blockade. The role of MDSCs in human STS tumors remains underexplored.
Natural Killer Cells
Natural Killer Cells is a type of immune cell that has granules (small particles) with enzymes that can kill tumor cells or cells infected with a virus. Therefore, these cells play an important role in cancer immunosurveillance. Studies of other tumors have evaluated the role of NK cells in the TME and the relationship between the infiltration of NK cells and the clinical outcome.
There have been a few studies of the NK cell function in STS. One of them detected infiltrating NK cells, generally in a low density, in some well-differentiated and dedifferentiated retroperitoneal liposarcoma tissues. Another study tumor-infiltrating NK cells were observed to correlate significantly with better disease-specific survival (DSS) in several sarcoma types.
In summary, a better understanding of immune cells status in STS will help more precise diagnosis and adapted treatment proposal, inspiring innovative therapy development.
Ref: Sousa, L.M.; Almeida, J.S.; Fortes-Andrade, T.; Santos-Rosa, M.; Freitas-Tavares, P.; Casanova, J.M.; Rodrigues-Santos, P. Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy. Cancers 2021, 13, 3885. https://doi.org/10.3390/ cancers13153885
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