Posted by 癌細胞不是爛草莓也有抗壓性
治療壓力反而讓它更會躲避免疫攻擊
免疫療法因重大貢獻獲得諾貝爾醫學獎，被視為癌症治療的新希望。然而最新研究顯示，癌細胞可不是爛草莓。在治療壓力下，它們反而會展現抗壓性，成功躲過免疫系統的追擊。
頭頸癌患者在接受標靶治療後，再接續免疫療法時，常常無法達到預期療效。研究團隊深入解析後揭露了一個關鍵原因：長期標靶治療帶來的「治療壓力」會讓癌細胞提高警覺，加速重塑腫瘤微環境，甚至主動關閉原本用來啟動免疫細胞的訊息通路，讓免疫療法失去效果。
造成癌細胞「抗壓性」的核心機制在於，當腫瘤長期受到標靶藥物壓制時，會分泌大量發炎因子 TNF-α，進而干擾 STAT1—這個原本負責啟動干擾素抗腫瘤基因的關鍵因子，形成所謂的「干擾素疲乏」（IFN-γ fatigue），讓免疫細胞對癌細胞的攻擊能力逐漸喪失。本論文的成果發表於 《Cell Reports Medicine》。
無獨有偶，研究團隊與中央研究院洪明奇院士合作、發表於《Advanced Science》的另一項研究，也揭露癌細胞會分泌一種名為RNase1的酵素，主動抑制T細胞等免疫細胞活性。這一機制在乳癌、肝癌、頭頸癌等多種癌別中皆被觀察到，顯示RNase1是跨癌別的重要免疫逃脫因子。
兩項研究共同描繪出一個清晰的圖像，癌細胞會「因壓力而成長」，不只被動抵抗，更會主動學習如何生存。他們一方面自行分泌蛋白削弱免疫攻擊，另一方面在治療壓力下反而更提高警覺，重新改寫免疫療法的訊號通路，展現出驚人的適應力。
不過儘管如此，瞭解這些癌細胞適者生存的方法，也讓醫師在治療排序、組合療法與生物標記選擇上提供重要依據。
楊慕華老師表示，免疫治療是癌症治療的重要里程碑，但如何克服抗性、提升療效仍是臨床最大挑戰。瞭解腫瘤在治療壓力下的適應性變化，未來可望透過生物標記導引治療順序與組合策略，提升免疫治療的成功率。
Researchers have identified adaptive traits in cancer cells that help tumors resist immunotherapy drugs after extended targeted treatment, revealing new hurdles to effective cancer treatment.
A research team at National Yang Ming Chiao Tung University discovered that immunotherapy’s success rate for head-and-neck tumors drops following prolonged exposure to cetuximab, a key drug in targeted therapies, the university said in a statement.
The team found that “therapeutic stress” might prompt cancer cells to produce an inflammatory mediator to block the immune system’s neural pathways, the statement said.
The study, “Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy,” was published in Cell Reports Medicine journal on Nov. 18, the university said.
After being subjected to extended immunotherapy, cancer cells release tumor necrosis factor-alpha, triggering a previously unknown process named STAT1 lysine 637 acetylation, which disrupts the function of interferon gamma, the statement said.
The interferon is crucial to the immune system’s functioning and declining responsiveness to it results in “interferon fatigue,” a mechanism that reduces the effectiveness of targeted therapy, it said.
Fatigued immune cells lose their aggression toward the tumor, it said.
In a related study conducted in collaboration with Academia Sinica, the team also observed that cancer cells produced the ribonuclease 1 enzyme, a substance that suppresses T lymphocytes, or T-cells, which fight cancer and other diseases, the university said.
The mechanism is seen in liver, breast and head-and-neck cancers, suggesting a common explanation for tumors capable of escaping detection and response by the immune system, it said.
The research conducted with Academia Sinica, “Ribonuclease 1 induces T-cell dysfunction and impairs CD8+ T-cell cytotoxicity to benefit tumor growth through hijacking STAT1,” was published in the Advanced Science journal on April 3 last year, the university said.
The National Yang Ming Chiao Tung University study shows that cancer cells are surprisingly adaptable to medical strategies and can develop countermeasures that defeat attempts at treatment, the statement said, quoting Yang Muh-hwa (楊慕華), a professor of clinical medicine who headed the university’s research team and was a corresponding author of the Academia Sinica study.
Understanding the mechanisms tumors employ to defeat immunotherapy — which is hailed as a milestone in cancer treatment — would help doctors use biomarker-guided sequences and combinations to improve outcomes, Yang said.
焦點新聞-癌細胞不是爛草莓也有抗壓性-國立陽明交通大學
Study shows traits in cancer cells help tumors resist drugs – Taipei Times