TY - JOUR
T1 - High HPK1+PD-1+TIM-3+CD8+ T cells infiltration predicts poor prognosis to immunotherapy in NSCLC patients
AU - Zhang, Jingxin
AU - Ren, Ziyuan
AU - Hu, Yun
AU - Shang, Shijie
AU - Wang, Ruiyang
AU - Ma, Jiachun
AU - Zhang, Zengfu
AU - Wu, Meng
AU - Wang, Fei
AU - Yu, Jinming
AU - Chen, Dawei
N1 - Publisher Copyright:
© 2023 Elsevier B.V.
PY - 2024/1/25
Y1 - 2024/1/25
N2 - At present the efficacy of immune checkpoint inhibitors (ICIs) remains limited. The lack of responsiveness in certain patients may be attributed to CD8+ T cell exhaustion within the tumor microenvironment (TME). Hematopoietic progenitor kinase 1 (HPK1) has been identified as a mediator of T cell dysfunction, leading to our hypothesis that HPK1 positive exhausted CD8+ T cells could serve as a predictor for ICIs' efficacy in NSCLC patients, and potentially indicate key cellular subset causing ICIs resistance. Here, we retrospectively collected tumor tissue samples from 36 NSCLC patients who underwent first-line immunotherapy. Using multiplex immunohistochemistry, we visualized various PD-1+CD8+ T cell subsets and explore biomarkers for response. The analysis endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS), correlating them with levels of cell infiltration or effective density. We found that the proportion of PD-1+CD8+ T cell subsets did not align with predictions for ORR, PFS, and OS. Conversely, a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells was identified as an independent risk factor for both PFS (P = 0.019) and OS (P = 0.03). These cells were found to express the highest levels of Granzyme B, and the secretion of Granzyme B in CD8+ T cell subsets was related to TCF-1. In conclusion, these data suggest that a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells correlates with poor clinical outcomes in NSCLC patients receiving immunotherapy. These cells may represent terminally exhausted T cells that fail to respond to ICIs, thereby laying the groundwork for the potential integration of HPK1 inhibitors with immunotherapy to enhance treatment strategy.
AB - At present the efficacy of immune checkpoint inhibitors (ICIs) remains limited. The lack of responsiveness in certain patients may be attributed to CD8+ T cell exhaustion within the tumor microenvironment (TME). Hematopoietic progenitor kinase 1 (HPK1) has been identified as a mediator of T cell dysfunction, leading to our hypothesis that HPK1 positive exhausted CD8+ T cells could serve as a predictor for ICIs' efficacy in NSCLC patients, and potentially indicate key cellular subset causing ICIs resistance. Here, we retrospectively collected tumor tissue samples from 36 NSCLC patients who underwent first-line immunotherapy. Using multiplex immunohistochemistry, we visualized various PD-1+CD8+ T cell subsets and explore biomarkers for response. The analysis endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS), correlating them with levels of cell infiltration or effective density. We found that the proportion of PD-1+CD8+ T cell subsets did not align with predictions for ORR, PFS, and OS. Conversely, a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells was identified as an independent risk factor for both PFS (P = 0.019) and OS (P = 0.03). These cells were found to express the highest levels of Granzyme B, and the secretion of Granzyme B in CD8+ T cell subsets was related to TCF-1. In conclusion, these data suggest that a high infiltration of HPK1+PD-1+TIM-3+CD8+ T cells correlates with poor clinical outcomes in NSCLC patients receiving immunotherapy. These cells may represent terminally exhausted T cells that fail to respond to ICIs, thereby laying the groundwork for the potential integration of HPK1 inhibitors with immunotherapy to enhance treatment strategy.
KW - CD8+ T cells
KW - Hematopoietic progenitor kinase 1
KW - Immunotherapy
KW - Non-small cell lung cancer
KW - Prognosis
UR - http://www.scopus.com/inward/record.url?scp=85179956925&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85179956925&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2023.111363
DO - 10.1016/j.intimp.2023.111363
M3 - Article
C2 - 38101218
AN - SCOPUS:85179956925
SN - 1567-5769
VL - 127
JO - International Immunopharmacology
JF - International Immunopharmacology
M1 - 111363
ER -