Study sheds additional light on cancer immunotherapy | 2021-07-09
Translational-controlled tumor protein (TCTP) is an immunomodulator that initiates the development of an inflammatory medium in the tumor microenvironment, where TCTP regulates the high activity of myeloid-derived suppressor cells (MDSC), the researchers reported.
The team also demonstrated that therapeutic targeting of TCTP could be an effective approach to limit the growth and / or metastasis of residual cancer cells in cancers that relapse or are refractory to immunotherapy after ablation, they reported in the July 8, 2021 edition of Natural immunology.
“We believe this is the first study to show the role of extracellular TCTP in the regulation of [microenvironment] and block it with the TCTP inhibitor, dihydroartemisinin (DHA), or a monoclonal antibody (MAb) that we developed against a human TCTP peptide, suppressed tumor growth in vivo, ”said Tadatsugu Taniguchi, study co-lead.
Despite promising clinical results with cancer immunotherapy, many patients are resistant to immune checkpoint blockade (ABI), largely because of barriers imposed by the microenvironment, which plays multiple essential roles in prevention, development and progression of tumors.
“The effectiveness of ICB depends on the type of tumor and tissue, but overall treatment with ICB is considered to be effective in about 20-30% of tumors,” said the professor and chair of the centre’s inflammation department. of Research for Advanced Science and Technology of University of Tokyo. “However, colorectal cancers (CRCs) are almost all resistant to ABI, except those with a mismatch repair deficit or high levels of microsatellite instability, suggesting that our MAb may be more effective for these cancers, ”he said. BioWorld Science.
The microenvironment also determines whether a tumor is destined to be eliminated or to escape, with non-inflamed or highly immunosuppressive microenvironments having a poor prognosis and worse treatment outcomes, while inflamed tumors favorably correlate with outcomes.
The microenvironment may also interfere with the effectiveness of other immunotherapies, including adoptive cell therapy and IL-2, and confer resistance to conventional cytotoxic chemotherapy.
Notably, the high densities of MDSC in the microenvironment promote tumor progression via multiple suppressive mechanisms, including suppression of lymphocyte function and physically disturbed tumor infiltration.
MDSCs are a major component of immune cells in the microenvironment, which suppress anti-tumor lymphocyte function and trafficking to the tumor.
Two major subsets of MDSC, both apparently differentiated from a common granulocyte / monocyte progenitor cell, have been identified and extensively studied in mice and humans.
Polymorphonuclear MDSCs (PMN-MDSCs) are morphologically similar to neutrophils, while monocytic MDSCs (M-MDSCs) resemble monocytes and differentiate into tumor associated macrophages (TAMs).
Elevated levels of MDSC are seen in almost all malignant tumors and are directly correlated with more advanced cancers, metastasis and poor prognosis, but despite extensive study, the dynamics of MDSC in the microenvironment remain poorly understood.
Another defining characteristic of the microenvironment is the low levels of nutrients and oxygen due to the metabolic demands of tumor growth. Under these conditions, the death of tumor cells results in the ectopic release of immunomodulatory molecules, collectively called damage-associated molecular motifs (DAMPs).
DAMPs are involved in sterile inflammation under physiological conditions, but our understanding of their role in the microenvironment, which could lead to the development of new cancer therapies, remains poorly understood.
In the new Natural immunology study, researchers led by Taniguchi and Hideyuki Yanai, associate professor in his laboratory, showed that TCTP released by dying tumor cells was an immunomodulator essential for the complete accumulation of the MDSC microenvironment.
“We generated an SL4 colon carcinoma cell line deficient in TCTP to analyze the immune cell population and their activation during tumor growth, while also generating and analyzing SL4 tumor cells that produce TCTP extracellularly”, Taniguchi said.
“The percentage of PMN-MDSC in the tumor microenvironment was found to be significantly reduced in tumors of TCTP-deficient cells compared to those of control cells,” he said. BioWorld Science.
“The opposite result was observed in cells expressing TCTP extracellularly, where enhancement of extracellular TCTP function significantly accelerated tumor growth.”
The researchers also demonstrated that extracellular TCTP mediated the recruitment of the microenvironmental population of PMN-MDSC via activation of the Toll-like receptor 2 (TLR2) and that inhibition of TCTP with DHA or neutralizing MAb suppressed in a manner that significant accumulation of PMN-MDSC and tumor growth.
“We showed for the first time that TCTP activates TLR2 and induces the expression of cytokines, including CXCL1 [C-X-C motif ligand 1] and CXCL2, which are important in the migration of PMN-MDSCs into the microenvironment, ”said Taniguchi.
“In fact, TCTP failed to induce the genes for these chemokines in cells lacking TLR2 or MyD88, an essential moderator of TLR2 signaling, while chemokine production was markedly suppressed in cell tumors. deficient in TCTP. “
In human cancers, researchers have demonstrated an elevation of TCTP and an inverse correlation of TCTP gene assay with anti-tumor immune signatures and clinical prognosis.
“Serum TCTP levels in patients with CRC were found to be significantly higher than those in the control group,” Taniguchi said.
“Our analysis using [The Cancer Genome Atlas] The TCGA database revealed amplification of the TCTP gene allele in approximately 5% of CRC patients, and that the level of TCTP mRNA expression correlated with the TCTP gene copy number ” , did he declare.
“We also found a negative correlation between the expression levels of TCTP and those of cytotoxic T lymphocytes, markers of natural killer cells and of cytolytic activity.”
Collectively, these results shed light on a previously poorly understood mechanism of MDSC dynamics in the tumor microenvironment, offering a new rationale for cancer immunotherapy, which may have important therapeutic implications.
“Although therapeutic strategies targeting MDSCs have not yet been established, our results could aid the development of such immune therapies, while the combination of TCTP inhibitors and ICB could further improve antitumor efficacy,” Taniguchi said.
“Our results may also have implications for conventional chemo / radiotherapy, which kills large numbers of tumor cells, which is known to have immunogenic or immunosuppressive consequences, as DAMPs can suppress anti-tumor immunity.”
Going forward, “because suppressing TCTP may be effective in inhibiting the growth and metastasis of residual tumor cells, we need to identify the types of tumors that can be treated effectively using this modality, while increasing the potency of MAbs neutralizing TCTP also represents a challenging future. “