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    Home > Active Ingredient News > Antitumor Therapy > Professor Zhou Caicun CameL research: The co-expression of different tumor immune microenvironment markers has the predictive value of potential immune combination therapy

    Professor Zhou Caicun CameL research: The co-expression of different tumor immune microenvironment markers has the predictive value of potential immune combination therapy

    • Last Update: 2023-01-05
    • Source: Internet
    • Author: User
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    The research results of Zhenhe Technology and the team of Professor Zhou Caicun of Shanghai Pulmonary Hospital affiliated to Tongji University were published in "Cancer Communications", IF:15.
    283
    .
    In this study, Zhen and Landis products were used for multiplex immunofluorescence (mIF) detection
    .


    Guide


    PD-1 inhibitors in combination with chemotherapy have become the new standard of the standard for first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), but nearly half of patients still do not benefit
    from this combination therapy.
    To further expand the population benefiting from PD-1 inhibitors in combination with chemotherapy, it is important
    to find reliable predictive biomarkers.
    However, neither PD-L1 expression nor single biomarkers such as TMB predicted the efficacy of
    combination therapy.
    Therefore, by detecting the expression level of tumor immune microenvironment biomarkers, this study explored the predictive value
    of a reasonable combination of different markers on the efficacy of PD-1 inhibitors combined with chemotherapy in patients with advanced NSCLC.


    1

    study

    Overview


    Patient condition


    A total of 144 patients with stage III.
    B-IV.
    non-squamous NSCLC who were newly treated were included, of which 77 received the PD-1 inhibitor carrelizumab in combination with chemotherapy and 67 received chemotherapy alone, and the objective response rate (ORR) of carrelizumab combined with chemotherapy was significantly higher than that in the chemotherapy alone group (59.
    7% vs 37.
    3%, P=0.
    007).


    Sample testing


    Multiplex immunofluorescence (mIF) based on multiplex immunofluorescence (mIF) technology was used to detect and analyze
    immunomicroenvironmental biomarkers (including PDL1, CD8, CD68, CD4 and FOXP3) in tissue samples prior to treatment.


    Table 1 Clinical baseline characteristics of 144 patients with NSCLC


    2

    The essential

    Study results


    The CD8/PD-L1 and CD68/PD-L1 co-expression levels in the responder group in the carrelizumab plus chemotherapy group were significantly higher than those in the non-responder group, and no significant difference
    was found in the chemotherapy alone group.


    This study first evaluated the correlation
    between expression levels (positive cell density and percentage of positive cells) and objective responses of single and co-expression markers (positive cell density and percentage of positive cells) in responders (CR+PR patients) and non-responders (SD+PD patients) in the carrelizumab plus chemotherapy group.



    Single markers (PD-L1, CD8, CD68, CD4, FOXP3)


    The PD-L1-positive cell density (P=0.
    013), the percentage of positive cells (P=0.
    020), CD8-positive cell density (P=0.
    046) and CD68-positive cell percentage (P=0.
    048) of the responders were significantly higher than those of the nonresponders
    .
    The expression levels of CD4 and FOXP3 were not correlated with objective response (Figure 1-B).


    Figure 1-B Correlation between single marker expression levels and therapeutic efficacy



    Co-expression markers (CD8/PD-L1, CD68/PD-L1, CD4/FOXP3, CD8/CD68/PD-L1, CD4/FOXP3/PD-L1)


    The positive cell density and percentage of positive cells in the responders were significantly higher than those in the nonresponders, while the co-expression levels of CD4/FOXP3, CD8/CD68/PD-L1, and CD4/FOXP3/PD-L1 were similar
    between the responders and nonresponders.


    Figure 1-C Correlation between expression levels of co-expression markers and therapeutic efficacy


    In the carrelizumab combined with chemotherapy group, the ORR of patients with high coexpression levels of CD8/PD-L1 or CD68/PD-L1 was significantly higher.
    The PFS and OS of patients with high co-expression of CD8/PD-L1 and CD68/PD-L1 were significantly improved
    .


    Next, this study evaluated the correlation
    between different combinations of co-expression markers and clinical outcomes in the carrelizumab plus chemotherapy group.
    The results showed that high CD8/PD-L1 and high CD68/PD-L1 co-expression levels had better predictive value
    .



    CD8/PD-L1 co-expression group


    In the carrelizumab combined with chemotherapy group, the ORR of patients in the high CD8/PD-L1 co-expression group (n=39) was significantly higher than that in the low co-expression group (n=38) (71.
    8% vs 47.
    4%, P = 0.
    029; Figure 2-B).
    In the chemotherapy alone group, the ORR of CD8/PD-L1 high and low co-expression groups was similar (P > 0.
    05; Figure 2-B).


    Note: The high co-expression group is the percentage of positive cells ≥ median level of the analyzed population; The low co-expression group is the percentage < median level of positive cells in the population being analyzed<b10>.


    Figure 2-B Comparison between treatment response in patients with high and low levels of CD8/PD-L1 co-expression


    In the carrelizumab combined with chemotherapy group, PFS (P=0.
    002; Figure 2-C) and OS (P=0.
    006; Figure 2-D) were significantly prolonged
    in the high CD8/PD-L1 co-expression group.


    In the high CD8/PD-L1 co-expression group, PFS (P=0.
    003) and OS (P=0.
    032) were significantly longer
    in patients receiving carrelizumab combined with chemotherapy than those in the chemotherapy alone.
    In the low CD8/PD-L1 co-expression group, there was no significant difference in PFS and OS among patients receiving different treatment modalities (Figure 2 C-D).


    Fig.
    2 Comparison of PFS and OS in patients with high and low CD8/PD-L1 co-expression levels in C-D



    CD68/PD-L1 co-expression group


    Patients with high CD68/PD-L1 co-expression (n=39) also achieved better ORR (69.
    2% vs 50.
    0%, P=0.
    085; Figure 3-B) in the carrelizumab combined with chemotherapy group, but did not achieve statistical significance.
    In the chemotherapy alone group, the ORR of CD68/PD-L1 high and low co-expression was similar (P>0.
    05; Figure 3-B).


    Figure 3-B Comparison of treatment responses between patients with high and low CD68/PD-L1 co-expression


    In the carrelizumab combined with chemotherapy group, PFS (P=0.
    024; Figure 3-C) and OS (P=0.
    026; Figure 3-D) and low CD68/PD-L1 co-expression patients with high CD68/PD-L1 co-expression were significantly prolonged
    .


    In the high CD68/PD-L1 co-expression group, PFS (P=0.
    004; Figure 3-C) and OS (P=0.
    022; Figure 3-D) of patients receiving carrelizumab combined with chemotherapy were also significantly better than those receiving chemotherapy alone.
    In the low CD68/PD-L1 co-expression group, there was no significant difference in PFS and OS among patients receiving different treatment modalities (Figure 3 C-D).


    Fig.
    3 Comparison of PFS and OS in patients with high and low CD68/PD-L1 co-expression levels in C-D


    In addition, after adjusting the clinicopathological features, the predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression in the carrelizumab combined with chemotherapy group PFS and OS was still statistically significant
    .


    The proportion of TP53/KRAS co-mutations was higher in the CD8/PD-L1 or CD68/PD-L1 high co-expression group, and abundant PI3K and cell cycle pathway mutations
    were found in the CD8/PD-L1 co-expression positive group.


    Finally, this study evaluated tumor mutation characteristics
    at different co-expression levels of CD8/PD-L1 or CD68/PD-L1.
    The results showed that the incidence of TP53 or KRAS mutations was similar among patients with high and low CD8/PD-L1 or CD68/PD-L1 co-expression groups, but the TP53/KRAS co-mutation ratio in the CD8/PD-L1 or CD68/PD-L1 high co-expression group was significantly higher than that in the low co-expression group (both 13.
    0% vs 0.
    0%, P=0.
    023; Figure 4-A).


    The results of CNV analysis showed significant deletion of CD8/PD-L1 positive chromosomes 5p and 8q, local amplification of CD8/PD-L1-negative chromosomes 5p, 7p and 14q (Figure 4-B), and significant CNV
    was observed on chromosomes 8q, 10q, 12q and 14q in the CD68/PD-L1 positive and negative groups.


    In addition, compared with the negative group, a significant abundant PI3K (P=0.
    012; Figure 4-C) and cell cycle pathway mutations (P=0.
    021; Figure 4-D) were found in the CD8/PD-L1 positive group, while there was no difference between the CD68/PD-L1 positive and negative groups (P>0.
    05).


    Fig.
    4 Tumor mutation characteristics of CD8/PD-L1 co-expression positive and negative groups


    3

    small

    knot


    This study mainly explores the predictive value of the expression levels of tumor immune microenvironment biomarkers PD-L1, CD8, CD68, CD4, FOXP3 and their different combinations in patients with locally advanced or metastatic NSCLC treated with PD-1 inhibitors and chemotherapy
    .


    The results of the study showed:
    • Patients who responded to carrelizumab combined with chemotherapy had significantly higher
      levels of CD8/PD-L1 or CD68/PD-L1 co-expression.

    • In the carrelizumab plus chemotherapy group, high co-expression of CD8/PD-L1 or CD68/PD-L1 was significantly associated
      with PFS and OS prolongation.

    • Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression had significantly higher TP53/KRAS co-mutation ratios, and patients with positive CD8/PD-L1 co-expression had more abundant
      mutations in PI3K and cell cycle pathways.


    In summary, the biologically rational combination of tumor immune microenvironment markers, especially the co-expression of CD8/PD-L1 and CD68/PD-L1, may become a predictive biomarker for PD-1 inhibitors combined with chemotherapy in patients with locally advanced or metastatic NSCLC, and the relevant predictive value needs to be further verified
    by subsequent research.



    Original research results:

    Multiplexed imaging of tumor immune microenvironmental markers in locally advanced or metastatic non-small-cell lung cancer characterizes the features of response to PD-1 blockade plus chemotherapy; 

    doi:10.
    1002/cac2.
    12383


    Note: All images in the text are from Wu F y et al .
    Cancer Commun (Lond).
    2022 Nov 4.

    *This article is only used to provide scientific information to medical professionals and does not represent the views of this platform


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