Nature Communications: Zhejiang University Ye Zhaoming's team reveals the mechanism by which chemotherapy leads to tumor immune escape

Osteosarcoma is the most common primary bone malignancy
.
Since the 1970s, chemotherapy has significantly improved overall survival in patients with osteosarcoma
.
At present, surgery combined with neoadjuvant chemotherapy has become the standardized treatment
of osteosarcoma.
Combination chemotherapy regimens of cisplatin, doxorubicin, methotrexate, and ifosfamide have also been used for decades
.

Although chemotherapy significantly improves the therapeutic effect of osteosarcoma, the clinical prognosis of osteosarcoma is still not ideal
.
About one-third of osteosarcoma patients do not respond well to chemotherapy drugs, are prone to recurrence and metastasis, and have a 5-year survival rate of only 5-20%.

Chemotherapy resistance and immune evasion have become major challenges in osteosarcoma treatment, and as a result, more effective strategies are needed to improve patient survival
.

On October 23, 2022, Professor Ye Zhaoming's team from the Second Affiliated Hospital of Zhejiang University School of Medicine published a paper in Nature Communications entitled "Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune" Evasion's research paper
.

This study revealed the key mechanism of chemotherapy-induced macrophage phagocytosis inhibition, which induces macrophages to secrete IL-18, upregulate the expression of the amino acid transporter LAT2 in tumor cells, and then upregulate CD47 expression, inhibit the phagocytosis of macrophages, leading to immune escape
of tumor cells.

The study also showed that inhibition of LAT2 could enhance macrophage infiltration and phagocytosis of tumor cells by downregulating CD47 expression in tumor cells, and make mouse osteosarcoma sensitive
to chemotherapy drug doxorubicin treatment.

These findings advance our understanding of the mechanisms of chemotherapy resistance and highlight the potential of
interventions for LAT2-mediated amino acid uptake to enhance cancer treatment.

The ability of cancer cells to escape immunity plays a crucial role
in cancer recurrence and metastasis.
Although chemotherapy drugs partially clear tumor cells by stimulating the immune system, there is growing evidence that tumors after chemotherapy are more
resistant to tumor immunity.

Macrophages are the most abundant type of immune cells in osteosarcoma, and the relationship between their density and clinical outcomes remains ambivalent
.
Analysis of prechemotherapy osteosarcoma specimens showed that increased macrophage density was associated with metastasis inhibition and longer progression-free survival of metastasis, while studies of osteosarcoma specimens after chemotherapy showed that metastatic osteosarcoma patients had more macrophages
in their tumors than in patients with osteosarcoma without metastases.
These results suggest that during osteosarcoma chemotherapy, cancer cells enhance immune escape to macrophages through some unknown mechanism
.

CD47, a transmembrane protein encoded by the CD47 gene in the human body, belongs to the immunoglobulin superfamily
.
Since the 80s of the 20th century, CD47 has been found to be highly expressed
in a variety of human hematological tumors, bladder cancer, brain tumors and other solid tumors.

In 2009, Professor Irving Weissman of Stanford University School of Medicine published a paper in Cell showing that tumor cells have a high expression of CD47 and release Don't Eat Me signals by binding to the signaling regulatory protein α (SIRPα) on the surface of macrophages, thereby preventing tumor cells from being engulfed
by macrophages.

In osteosarcoma, CD47 expression levels in osteosarcoma tissue are usually higher than in surrounding normal tissue, and high expression of CD47 is associated
with poor survival in osteosarcoma patients.
By inhibiting CD47, activation of tumor-associated macrophages enhanced macrophage-mediated tumor cell clearance, inhibiting the growth and lung metastasis
of mouse osteosarcoma.
CD47 blockers have also shown promising activity
in patients with advanced blood cancers.
Clinical trials are currently being designed to evaluate whether inhibition of CD47 enhances response
to other immunotherapies in patients with osteosarcoma.

However, it is unclear
whether CD47 expression in osteosarcoma cells is regulated in the response to chemotherapy, thereby promoting tumor immune evasion.

Cancer cells need adequate nutrients to maintain their rapid growth and proliferation
.
Amino acid transporters are essential
for maintaining high levels of metabolism and protein synthesis in cancer cells.
Therefore, enhanced absorption
of amino acids by upregulating specific transporters has been observed in many primary human tumors, as well as in various cancer cell lines.

L-type amino acid transporters (LATs) are the primary sodium-independent transport systems
for neutral amino acids such as glutamine and leucine.
So far, four LATs (LAT1, LAT2, LAT3, and LAT4) have been identified, and blocking LAT1 has become an attractive strategy
in cancer treatment.
However, the relationship between amino acid uptake and tumor immune checkpoint regulation is unclear
.

In this study, the team found that CD47 was upregulated in osteosarcoma after chemotherapy, and this upregulation was associated
with mortality.

Mechanistically, chemotherapy promotes the secretion of interleukin 18 (IL-18) in macrophages, thereby upregulating the expression of LAT2 in tumor cells, thereby greatly enhancing the uptake of glutamine and leucine, which are two potent stimulants
of mTORC1.
Increased leucine levels and enhanced glutamine metabolism activate mTORC1 and subsequent c-Myc-mediated CD47 transcription
.
LAT2 deletion or treatment with LAT inhibitors can downregulate the CD47 expression of tumor cells, enhance macrophage infiltration and phagocytosis of tumor cells, and make mouse osteosarcoma sensitive
to chemotherapy drug doxorubicin treatment.

These findings reveal that the mutual regulation between macrophages and tumor cells plays a key role in tumor immune evasion and highlight the potential of
intervention in LAT2-mediated amino acid uptake to improve cancer treatment outcomes.

Original source:

Wang， Z.
， Li， B.
， Li， S.
et al.
Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion.
Nat Commun 13， 6308 (2022).
https：//doi.
org/10.
1038/s41467-022-34064-4.