Genetic or pharmacological inhibition of the PLC pathway potentiates antitumor immunity. (A–C) HLA affinity analysis of peptides identified by HLA IP-MS by Shapiro et al. in PDIA3 KO and WT cells. HLA-binding peptides were divided into three groups: those unique to or over-presented in PDIA3 KO cells (sgPDIA3-specific, n = 623), unique to or over-presented in WT cells (WT-specific, n = 4,739), and common peptides (n = 10,651). The binding affinity (nM) of peptides presented on HLA-A*02:01 (A), HLA-B*40:01 (B), or HLA-C*03:04 (C) was predicted by netMHCpan 4.1 and shown as log2-transformed values. The point represents the median of each group. ****P < 0.0001 by a Mann–Whitney U test. (D) Volume of WT or Pdia3 KO LLC tumors following treatment with LOC14 or vehicle control in WT C57BL/6 mice (n = 7–8 per group). Mice were treated with 350 μg LOC14 per mouse via intratumoral injection at days 6, 9, 12, and 15 after tumor implantation. Data are presented as the mean ± SEM. ns, not significant; ****P < 0.0001 by two-way ANOVA. Data are representative of two independent repeats. (E) Survival curve of WT or Pdia3 KO LLC tumors after LOC14 or vehicle treatment at days 6, 9, 12, and 15 after tumor implantation. Significance was evaluated by a log-rank (Mantel–Cox) test. ns, not significant; *P < 0.05. Data are representative of two independent repeats. (F and G) LLC tumor volume following treatment with LOC14 or vehicle control in Rag1 KO (F, n = 6–7 per group) and WT C57BL/6 mice (G, n = 5–6 per group). Mice were treated with 350 μg LOC14 per mouse via intratumoral injection every 3 days, starting at 4 days after tumor implantation, for a total of four injections. Data are presented as the mean ± SEM. ns, not significant; ****P < 0.0001 by two-way ANOVA. Data are representative of two independent experiments. (H) Multivariate Cox regression analysis of PLC gene alterations in a curated cancer cohort of 31,365 patients. Hazard ratios and P values for each gene alteration are shown. (I) Comparison of immune cell infiltration levels between WT and mutated CALR in UCEC. Each plot shows the LFC and P value for immune cell (CD8+ T cell subtypes and myeloid dendritic cell) infiltration level estimated from the indicated method, including TIMER and XCELL. (J) Differential immune infiltration levels between variant and WT B2M, ERAP1, PDIA3, TAP1, TAP2, and TAPBP in UCEC. Colors represent the LFC with significance levels denoted. LFC, log2 fold change.
Figure 5.

Genetic or pharmacological inhibition of the PLC pathway potentiates antitumor immunity. (A–C) HLA affinity analysis of peptides identified by HLA IP-MS by Shapiro et al. in PDIA3 KO and WT cells. HLA-binding peptides were divided into three groups: those unique to or over-presented in PDIA3 KO cells (sgPDIA3-specific, n = 623), unique to or over-presented in WT cells (WT-specific, n = 4,739), and common peptides (n = 10,651). The binding affinity (nM) of peptides presented on HLA-A*02:01 (A), HLA-B*40:01 (B), or HLA-C*03:04 (C) was predicted by netMHCpan 4.1 and shown as log2-transformed values. The point represents the median of each group. ****P < 0.0001 by a Mann–Whitney U test. (D) Volume of WT or Pdia3 KO LLC tumors following treatment with LOC14 or vehicle control in WT C57BL/6 mice (n = 7–8 per group). Mice were treated with 350 μg LOC14 per mouse via intratumoral injection at days 6, 9, 12, and 15 after tumor implantation. Data are presented as the mean ± SEM. ns, not significant; ****P < 0.0001 by two-way ANOVA. Data are representative of two independent repeats. (E) Survival curve of WT or Pdia3 KO LLC tumors after LOC14 or vehicle treatment at days 6, 9, 12, and 15 after tumor implantation. Significance was evaluated by a log-rank (Mantel–Cox) test. ns, not significant; *P < 0.05. Data are representative of two independent repeats. (F and G) LLC tumor volume following treatment with LOC14 or vehicle control in Rag1 KO (F, n = 6–7 per group) and WT C57BL/6 mice (G, n = 5–6 per group). Mice were treated with 350 μg LOC14 per mouse via intratumoral injection every 3 days, starting at 4 days after tumor implantation, for a total of four injections. Data are presented as the mean ± SEM. ns, not significant; ****P < 0.0001 by two-way ANOVA. Data are representative of two independent experiments. (H) Multivariate Cox regression analysis of PLC gene alterations in a curated cancer cohort of 31,365 patients. Hazard ratios and P values for each gene alteration are shown. (I) Comparison of immune cell infiltration levels between WT and mutated CALR in UCEC. Each plot shows the LFC and P value for immune cell (CD8+ T cell subtypes and myeloid dendritic cell) infiltration level estimated from the indicated method, including TIMER and XCELL. (J) Differential immune infiltration levels between variant and WT B2M, ERAP1, PDIA3, TAP1, TAP2, and TAPBP in UCEC. Colors represent the LFC with significance levels denoted. LFC, log2 fold change.

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