1. Causality between immune cell traits and therapeutic efficacy.
Using univariate Mendelian randomized analysis, we identified 28 immune cell traits (Fig. 3) significantly related to the efficacy of platinum drugs, including 16 protective factors and 12 risk factors. Among them, CD19 on CD24 + CD27 + B cell (OR = 0.598, P = 0.004) is the most significant immune cell trait (Fig. 3a). Among the risk factors (Fig. 3b), the immune cell traits with extreme significant (p < 0.01) include Granulocyte Absolute Count (OR = 11.844, P = 0.002) and CD20 on B cell (OR = 1.299, P = 0.003), HLA DR + + monocyte % leukocyte (OR = 2.938, p = 0.008) and CD4 on CD45RA + CD4 + T cell (OR = 1.867, p = 0.009). At the same time, we also found that the surface antigen CD39 is a protective factor of therapeutic efficacy in CD4 + T cells and CD8 + T cells. On the contrary, the expression of HLA DR in monocytes or T cells is a dangerous signal for therapeutic efficacy.
2. Causal relationship between immune cell traits and platinum drugs affecting hepatic and renal injury.
Using the same Mendel randomized analysis method, we found 26 immune cell traits significantly related to platinum drugs' hepatic injury and 38 immune cell traits significantly related to platinum drugs' renal injury (Fig. 4), including 14 protective factors for hepatic injury (Fig. 4a), 12 risk factors for hepatic injury (Fig. 4b), 24 protective factors for renal injury (Fig. 4c) and 14 risk factors (Fig. 4d) for renal injury. Among the protective factors of liver injury, the extreme significant traits (p < 0.01) include HLA DR + CD8 + T cell % lymphocyte (OR = 0.427, p = 7.551E-04), CD20 on IgD- CD38 + B cell (OR = 0.015, p = 0.003), HLA DR + CD8 + T cell % T cell (OR = 0.471, p = 0.003), CD3 on activated CD4 regulatory T cell (OR = 0.389, p = 0.007), CD3 on Effector Memory CD4 + T cell (OR = 0.389, p = 0.007). Among the risk factors of hepatic injury, the immune cell traits with p < 0.01 are CD27 on CD24 + CD27 + B cell (OR = 2.548, p = 0.002), B cell % lymphcyte (OR = 2.976, p = 0.003), CD62L on granulocyte (OR = 5.099, p = 0.007). There are five extremely significant immune cell traits (p < 0.01) of protective factors for renal injury, which are Central Memory CD4-CD8- T cell % T cell (OR = 0.007,p = 7.830E-04), CD8 on Central Memory CD8 + T cell (OR = 0.116,p = 0.003), BAFF-R on IgD- CD38 + B cell (OR = 0.086, p = 0.006), CD4-CD8- Natural Killer T % T cell (OR = 0.068,p = 0.007), CD25 + + CD45RA- CD4 not regulatory T cell Absolute Count (OR = 0.041,p = 0.007). The risk factors of renal injury are extremely significant (p < 0.01) as follows CD28 + CD45RA + CD8 + T cell % T cell (OR = 1.095, p = 0.003), CD39 on CD39 + secreting CD4 regulatory T cell (OR = 28.729, p = 0.009), CD3 on CD39 + resting CD4 regulatory T cell (OR = 3.024, p = 0.009).
We found that the more of HLA DR + T cells absolute count, the more the proportion of HLA DR + T cells in T cells and lymphocytes, the greater the protective effect on hepatic injury, but HLA DR + + monocytes are risk factors for hepatic injury. Among the protective factors of renal injury, BAFF-R is our key concern, and it is expressed on various subtypes of B cells, including memory B cells, IgD + B cells, IgD- B cells, switched B cells and unswitched B cells. The expressions of CD3 and CD39 on CD4 regulatory T cell are risk factors for renal injury.
3. Causal relationship between immune cell traits and platinum drugs affecting gastrointestinal upset and cutaneous toxicity.
As shown in the Fig. 5, There are 30 immune cell traits related to gastrointestinal upset, 15 protective factors (Fig. 5a) and 15 risk factors (Fig. 5b) for gastrointestinal upset, and 31 immune cell traits related to cutaneous toxicity, including 21 protective factors (Fig. 5c) and 10 risk factors (Fig. 5d) for cutaneous toxicity. Among them, the protective factors of gastrointestinal upset are extreme significant (p < 0.01) include CD4 on monocyte (OR = 0.308, p = 0.001), CD4 on CD28 + CD4 + T cell (OR = 0.146, p = 0.002), CD19 on naïve-mature B cell (OR = 0.595, p = 0.002), CD127- CD8 + T cell Absolute Count (OR = 0.236, p = 0.003), CD16- CD56 on Natural Killer T cell (OR = 0.318, p = 0.005). The risk factors of gastrointestinal upset are extreme significant (p < 0.01) include CD34 on Hematopoietic Stem Cell (OR = 1.466,p = 0.003), CD45RA + CD28- CD8 + T cell Absolute Count (OR = 1.000,p = 0.004), CD33 on CD14 + monocyte (OR = 3.051,p = 0.007), SSC-A on HLA DR + CD4 + T cell (OR = 2.335,p = 0.009). There are 10 immune cell traits that are extreme significant (p < 0.01) in cutaneous toxicity protection factors, and the first three are CD19 on IgD + CD24 + B cell (OR = 0.520, p = 0.001), CD66b on CD66b + + myeloid cell (OR = 0.334, p = 0.001), CD3 on resting CD4 regulatory T cell (OR = 0.380, p = 0.002), and other characters can refer to Fig. 5D. The risk factors of cutaneous toxicity are extreme significant (p < 0.01) include CD27 on memory B cell (OR = 1.590, p = 0.004) and CD28-CD4-CD8- T cell % CD4-CD8- T cell (OR = 4.385, p = 0.009).
We found that naïve-mature B cell is a protective factor for gastrointestinal upset and cutaneous toxicity. The expression of BAFF-R on different B cells has different effects on gastrointestinal upset. For example, the expression on IgD- CD27- B cell, CD20- B cell and IgD- CD24- B cell is a protective factor, but the expression on transitional B cell and IgD + CD38 + B cell is a risk factor. At the same time, the expression of CD19 on different subtypes of B cells is a protective factor for cutaneous toxicity, such as in memory B cell, IgD + B cell and naïve-mature B cell. In particular, we found that Plasmacytoid Dendritic Cell is a risk factor for cutaneous toxicity.
4. Quantitative relationship between immune cell traits and efficacy and adverse reactions of platinum drugs.
Using two-sample Mendel randomized analysis, we determined the causal relationship between immune cell traits and the efficacy and adverse reactions of platinum drugs and quantified these results (Fig. 6). We divide all traits into six categories, namely T cells, B cells, dendritic cells, natural killer cells, monocytes and others, in which T cells account for 42% of the total traits, B cells account for 26% of the total traits, and the remaining traits account for about 30%.
we found that more than half of the influencing factors are the outcome of T cell-related traits, such as efficacy, hepatic injury and renal injury. As a leader in cellular immunity, T cells have no doubt about their influence on substantive organs. Meanwhile the two outcomes most affected by B cell traits are gastrointestinal upset and cutaneous toxicity.