TY - JOUR
T1 - Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes
AU - Lee, Hyo Jung
AU - Song, Kwon Ho
AU - Oh, Se Jin
AU - Kim, Suyeon
AU - Cho, Eunho
AU - Kim, Jungwon
AU - Park, Yun gyu
AU - Lee, Kyung Mi
AU - Yee, Cassian
AU - Song, Seung Hwa
AU - Chang, Suhwan
AU - Choi, Jungmin
AU - Jung, Sang Taek
AU - Kim, Tae Woo
N1 - Funding Information:
This work was supported by funding from the National Research Foundation of Korea (NRF-2020R1A2B5B03095410, NRF-2019R1A4A1029000, NRF-2019M3A9A8066884, and NRF-2021R1C1C2013395), Korea Drug Development Fund (HN21C0486), and Korean Foundation for Cancer Research (KFCR-2020-004).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Immunotherapy has emerged as a powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be targeted by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop combination strategies. Here, using the transcriptome data of patients, and immune-refractory tumor models, we identify TCTP as an immune-resistance factor that correlates with clinical outcome of anti-PD-L1 therapy and confers immune-refractory phenotypes, decreased T cell trafficking to the tumor and resistance to cytotoxic T lymphocyte-mediated tumor cell killing. Mechanistically, TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, treatment with dihydroartenimsinin, the most effective agent impending the TCTP-mediated-refractoriness, synergizes with T cell-mediated therapy to control immune-refractory tumors. Thus, our findings suggest a role of TCTP in promoting immune-refractoriness, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.
AB - Immunotherapy has emerged as a powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be targeted by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop combination strategies. Here, using the transcriptome data of patients, and immune-refractory tumor models, we identify TCTP as an immune-resistance factor that correlates with clinical outcome of anti-PD-L1 therapy and confers immune-refractory phenotypes, decreased T cell trafficking to the tumor and resistance to cytotoxic T lymphocyte-mediated tumor cell killing. Mechanistically, TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, treatment with dihydroartenimsinin, the most effective agent impending the TCTP-mediated-refractoriness, synergizes with T cell-mediated therapy to control immune-refractory tumors. Thus, our findings suggest a role of TCTP in promoting immune-refractoriness, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.
UR - http://www.scopus.com/inward/record.url?scp=85128409990&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29611-y
DO - 10.1038/s41467-022-29611-y
M3 - Article
C2 - 35440620
AN - SCOPUS:85128409990
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2127
ER -
