Study casts further light on cancer immunotherapy

Translationally controlled tumor protein (TCTP) is an immunomodulator that initiates development of an inflammatory milieu in the tumor microenvironment, where TCTP regulates high myeloid-derived suppressor cell (MDSC) activity, researchers have reported.

The team also demonstrated that therapeutically targeting TCTP might be an effective approach to limit growth and/or metastasis of residual cancer cells in cancers that relapse or are refractory to immunotherapy following ablation, they reported in the July 8, 2021, edition of Nature Immunology.

"We believe this is the first study to show the role of extracellular TCTP in regulating the [microenvironment] and that blocking it with the TCTP inhibitor, dihydroartemisinin (DHA), or a monoclonal antibody (MAb) that we developed against a human TCTP peptide, suppressed in vivo tumor growth," said study co-leader Tadatsugu Taniguchi.

Despite promising clinical outcomes with cancer immunotherapy, many patients are refractory to immune checkpoint blockade (ICB), due largely to obstacles imposed by the microenvironment, which plays multiple critical roles in tumor prevention, development and progression.

"ICB efficacy depends on the type of tumor and tissue, but overall ICB treatment is considered effective in approximately 20-30% of tumors," said the professor and chair of the Department of Inflammology in the Research Center for Advanced Science and Technology at the University of Tokyo. "However, colorectal cancers (CRCs) are almost all resistant to ICB, except those with mismatch-repair deficiency or high levels of microsatellite instability, suggesting our MAb may be more effective for such cancers," he told BioWorld Science.

The microenvironment also determines whether a tumor is fated for elimination or escape, with noninflamed or highly immunosuppressive microenvironments having poor prognosis and worse treatment outcomes, while inflamed tumors correlate favorably with outcomes.

The microenvironment may also impair efficacy of other immunotherapies, including adoptive cellular and IL-2 therapy, and confer resistance to conventional cytotoxic chemotherapy.

Notably, high MDSC densities in the microenvironment promote tumor progression via multiple suppressive mechanisms, including lymphocyte function suppression and physically disrupted tumor infiltration.

MDSCs comprise a major component of the microenvironment's immune cells, which suppress antitumor lymphocyte function and trafficking to the tumor.

Two major MDSC subsets, 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 to tumor-associated macrophages (TAMs).

Elevated MDSC levels are seen in almost all malignancies and directly correlate with more advanced cancers, metastasis and poor prognosis, but despite extensive study, microenvironment MDSC dynamics remain poorly understood.

Another microenvironment-defining feature concerns low nutrient and oxygen levels due to the metabolic demands of tumor growth. Under these conditions, tumor cell death results in ectopic release of immunomodulatory molecules, collectively termed damage-associated molecular patterns (DAMPs).

DAMPs mediate sterile inflammation under physiologic conditions, but our understanding of their role in the microenvironment, which might lead to the development of new cancer therapeutics, remains poorly understood.

In the new Nature Immunology study, researchers led by Taniguchi and Hideyuki Yanai, an associate professor in his lab, showed that TCTP released by dying tumor cells was an immunomodulator crucial to full-blown MDSC microenvironment accumulation.

"We generated a TCTP-deficient SL4 colon carcinoma cell line to analyze the immune cell population and their activation during tumor growth, while also generating and analyzing SL4 tumor cells that produce TCTP extracellularly," said Taniguchi.

"The percentage of PMN-MDSCs in the tumor microenvironment was found to be significantly reduced in tumors of TCTP-deficient cells compared to those of control cells," he told BioWorld Science.

"The opposite result was observed in cells expressing TCTP extracellularly, wherein enhancement of extracellular TCTP function significantly accelerated tumor growth."

The researchers also demonstrated that extracellular TCTP mediated recruitment of the microenvironmental PMN-MDSC population via activation of Toll-like receptor 2 (TLR2) and that TCTP inhibition with DHA or the neutralizing MAb significantly suppressed PMN-MDSC accumulation and tumor growth.

"We showed for the first time that TCTP activated TLR2 and induced the expression of cytokines, including CXCL1 [C-X-C motif ligand 1] and CXCL2, which are important in migration of PMN-MDSCs into the microenvironment," said Taniguchi.

"In fact, TCTP failed to induce these chemokines' genes in cells lacking TLR2 or MyD88, an essential moderator of TLR2 signaling, while chemokine production was markedly suppressed in tumors of TCTP-deficient cells."

In human cancers, the researchers demonstrated an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis.

"Serum TCTP levels in CRC patients were found to be significantly higher than those in the control group," Taniguchi said.

"Our analysis using [The Cancer Genome Atlas] TCGA database revealed amplification of the TCTP gene allele in about 5% of CRC patients, and that the TCTP mRNA expression level correlated with the TCTP gene copy number," he said.

"We also found a negative correlation between TCTP expression levels and those of cytotoxic T lymphocytes, natural killer cell markers and cytolytic activity."

Collectively, these findings cast 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 treatment implications.

Treatment implications

"Although therapeutic strategies targeting MDSCs have yet to be established, our findings may help in the development of such immune therapies, while combining TCTP inhibitors and ICB may further enhance antitumor efficacy," said Taniguchi.

"Our findings may also have implications for conventional chemo/radiotherapy, which kills large numbers of tumor cells, with this being known to have either immunogenic or immunosuppressive consequences, as DAMPs may suppress antitumor immunity."

In the future, "because TCTP suppression may be effective in inhibiting growth and metastasis of residual tumor cells, we need to identify those tumor types that can be effectively treated using this modality, while increasing the potency of TCTP-neutralizing MAbs also represents a future challenge."

Source