ICB免疫治疗超进展的一种解释

一、免疫治疗的CR应答者与起促癌反作用的超进展患者的T细胞浸润、TCR、核心免疫原性并无差异；超进展患者并没被免疫排斥，关键不在这里。
6 x$ l3 ?# \+ Q6 M% j《Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy》
Unexpectedly, patients with CR and patients with HPD demonstrated comparable levels of IFNγ and IRF1 as well as similar T cell clonal diversity, number of TCR clones, number of TCR reads, and CD8+ T cell infiltration (Figure 2A). Regulatory T cells, myeloid dendritic cells (DCs), and macrophages mediate immunosuppression in the tumor microenvironment via multiple mechanisms, such as the PD-L1-PD-1 pathway 40,41. Surprisingly, the levels of PDCD1 (PD-1), FOXP3, and CD68 were also comparable between patients who had CR and HPD in response to ICB (Figure 2A). To orthogonally confirm this observation, we evaluated CD8+ T cells in tumors in metastatic melanoma (Cohort 1) and NSCLC patients (Cohort 2) who had available tissues. Multiplex immunohistochemistry showed comparable levels of tumor CD8+ T cell infiltration between CR and HPD patients with melanoma (Figures 2B and 2C) and NSCLC (Figures 2D and 2E). These data indicate that patients with HPD are unexpectedly not immune excluded.
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( Y0 A" L) K$ A+ L1 @0 f- A二、CR应答者与超进展患者的差别在于超进展患者的 FGF2、Wnt/β-catenin、 and stemness/invasiveness 通路被激活了，关键在这里。
Given the lack of significant differences in the immune composition of patients who responded completely versus those who developed HPD following receipt of ICB, we then evaluated common oncogenic pathways 18. Gene signatures for several common oncogenic signaling pathways, including Sonic Hedgehog, Hippo, KRAS, NOTCH, and EGF were similarly expressed in patients with HPD and CR (Figure 2F). Interestingly, we found that FGF2 and Wnt-β-catenin gene signatures were highly expressed in patients who developed HPD as compared to patients who underwent a CR (Figures 2F and S2F). We detected comparable levels of expression of EGFR, MDM2, and MDM4, but higher levels of tumor stemness and invasiveness in HPD as compared to CR (Figure S2G). We found one case with BRAF mutation and no cases with MDM2, MDM4, and EGFR amplification in this cohort (Figure S2H). The results suggest that FGF2, Wnt-β-catenin, and stemness/invasiveness pathways may be activated in patients with HPD. To validate this finding, we examined FGF2 and MYC, surrogates for FGF signaling and β-catenin signaling, in tumors from patients with melanoma and NSCLC who had CR or HPD following receipt of ICB. Multiplex immunohistochemistry revealed nuclear FGF2 indicative of active FGF2 signal transduction 42 and MYC expression (Figure 2G, upper panel). Quantitation revealed higher levels of FGF2+MYC+ melanoma cells in patients with a HPD phenotype as compared to patients with a CR phenotype (Figure 2H). Similar results were obtained in patients with NSCLC (Figure 2I, upper panel and Figure 2J). Furthermore, we performed multiplex immunofluorescence staining for CD133, a marker for stemness in cancer tissues from patients with CR and HPD. There was higher frequency of CD133high tumor cells (Figures 2G, 2I, lower panels, and Figure 2H) and FGF2highCD133high tumor cells (Figures S2I and S2J) in HPD patients as compared to CR patients. The data suggest that immunotherapy-associated HPD is associated with activation of the FGF2 and β-catenin oncogenic pathways as well as increased tumor stemness.
/ F, y/ C# V7 N' {# }& @! n8 k要用ICB免疫治疗的患者，不妨先检测一下fgf2、β-catenin、cd133的表达情况，预估一下超进展的风险，采取一定的针对治疗。
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三、Trifluoperazine 抑制 cd133、β-catenin，改善免疫微环境
1、《Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer》
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
2、《Immune Microenvironment and Response in Prostate Cancer Using Large Population Cohorts》
. v! S7 q2 Z1 s, @CMap analysis was used to identify potential compounds and drugs targeting high IRS patients. Thioridazine, trifluoperazine, 0175029-0000, trichostatin A, and fluphenazine were potential targets for high IRS patients, and all the compounds inhibited PCa progression. Some of these compounds have been reported to suppress PCa growth in previous studies. Singh et al. reported that thioridazine inhibits outgrowth of androgen-independent PCa through TLK1/NEK1/DDR axis throughin vitro and in vivo experiments (44). Batra et al. reported that trifluoperazine inhibits PCa cell proliferation by regulating a calmodulin-mediated pathway (45). The findings of this study imply that these compounds limit PCa progression and affect the response rate of immunotherapy.

7 a7 z* I3 `: H! o& i/ F. g& D四、低分子肝素抑制fgf2活性；临床试验结果也表明了ICB免疫治疗联合肝素等抗凝药疗效更好。
1、《The influence of unfractionated and low-molecular weight heparins on the properties of human umbilical vein endothelial cells (HUVEC)》
3 s  r$ A, l3 n5 cHeparins, as anticoagulants widely used in the prophylaxis and treatment of many conditions connected with hypercoagulability, have a potent effect on the vascular endothelium. Unfractionated Heparin (UFH) is characterized by relatively low biological accessibility, short activity time, binding of numerous proteins, as well as unfavorable influence on endothelium and blood platelets. Low-Molecular Weight Heparins (LMWHs), formed by chemical and enzymatic UFH depolymerizations, show a significantly more favorable impact on endothelium, which was confirmed on the HUVEC cultures study models. The studies on the heparins' modulation of angiogenesis process proved the superiority of LMWHs over UFH. It was connected with a better deactivation of growth factors' receptors (e.g. for VEGF165, FGF-2). Comparing the effects of LMWHs and UFH on haemostatic and antiangiogenic properties of HUVEC, significant differences were found as well. A new effect, engaging these compounds in the pathomechanism of an excessive osteoclastogenesis via osteoprotegerin /RANKL/RANK pathway has been discovered recently.
2、《Improved survival of advanced melanoma patients receiving immunotherapy with concomitant antithrombotic therapy - A multicenter study on 2419 patients from the prospective skin cancer registry ADOReg》
; q3 ]2 d, E, y4 w9 p+ ]- JMethods: We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS).
( l0 u* |) M' p1 I3 v; hResults: A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301).