摘要:SHP2的变构抑制通过调节先天和适应性机制诱导pd -1敏感肿瘤的抗肿瘤免疫

E. Quintana, Kasia Mordec, R. Nichols, D. Wildes, C. Schulze, D. Myers, Mallika Singh, E. Koltun, A. Gill, S. Kelsey, M. Goldsmith, Jan Smith
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RMC-4550 did not inhibit growth in any of these cancer cell lines in vitro, suggesting that activity was not due to a tumor cell intrinsic antiproliferative effect. Rather, antitumor activity in vivo reflected modulation of murine host immune cell function. First, RMC-4550 did not inhibit tumor growth in immunocompromised Rag-2-deficient mice. Second, efficacy was significantly attenuated when CD8+T-cells were depleted in immunocompetent mice, suggesting that CD8+T-cells were important for tumor growth inhibition. Third, Shp2 inhibition had additive activity in combination with anti-CTLA4 or anti-PD-L1 treatment, resulting in complete tumor regression in some mice. Rechallenge studies also demonstrated the presence of immunologic memory induced by combination therapy. The additive activity with checkpoint blockade suggests an additional mechanism of action beyond inhibition of the checkpoint signal. Fourth, analysis of the immune landscape in the tumor microenvironment indeed revealed modulation of both adaptive and innate immune mechanisms. Similar to checkpoint blockade, RMC-4550 increased the frequency of CD8+T-cell infiltrates in tumors with a corresponding decrease in their PD-1 expression. In addition, Shp2 inhibition significantly shifted polarized macrophage populations by markedly increasing M1 and decreasing M2, effects not seen with anti-CTLA4 or anti-PD-L1. Collectively, these results suggest that SHP2 inhibition is not identical to that of checkpoint blockade and represents a novel investigational strategy that could leverage two antitumor mechanisms simultaneously: direct inhibition of cancer cell growth and modulation of the tumor microenvironment. Tumors that harbor oncogenic driver mutations sensitive to SHP2 and with established clinical sensitivity to checkpoint inhibitors could be of particular interest. Citation Format: Elsa Quintana, Kasia Mordec, Robert J. Nichols, David Wildes, Chris J. Schulze, Darienne R. Myers, Mallika Singh, Elena Koltun, Adrian Gill, Stephen Kelsey, Mark A Goldsmith, Jan A.M. Smith. Allosteric inhibition of SHP2 induces antitumor immunity in PD-1-sensitive tumors through modulation of both innate and adaptive mechanisms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. 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引用次数: 0

摘要

由PTPN11编码的蛋白酪氨酸磷酸酶SHP2是一种已知的癌症亚群的致癌驱动因子,也是RTK-RAS-MAPK通路的中心信号节点。遗传和药理学证据支持SHP2在驱动依赖于一系列激活的rtk、某些RAS和BRAF突变以及NF1功能丧失突变的癌细胞增殖中的作用。相比之下,SHP2在抗肿瘤免疫中的作用尚未得到很好的证实。SHP2结合免疫细胞中调控受体上磷酸化的ITIM和ITAM结构域,多个报告证实了SHP2/PD-1的物理相互作用。最近有人提出SHP2通过CD28的直接去磷酸化来转导PD-1抑制检查点信号。在这项研究中,我们发现一种由PD-1 ITAM中两个酪氨酸磷酸化的9-mers序列组成的肽(通过PEG8连接物连接)可以激活纯化的SHP2酶。我们还证明,与检查点抑制剂一样,SHP2的变构抑制可以激活报告基因PD-1/PD-L1中nfat介导的基因表达。基于这些发现,我们利用新型SHP2小分子变构抑制剂rmmc -4550,评估了SHP2抑制对小鼠宿主免疫细胞和体内肿瘤免疫微环境的影响。每日口服rmmc -4550可显著抑制三种对检查点阻断敏感的同基因肿瘤模型的肿瘤生长。抑制活性与检查点抑制相当,在某些情况下优于检查点抑制。rmmc -4550在体外没有抑制任何这些癌细胞系的生长,表明活性不是由于肿瘤细胞固有的抗增殖作用。相反,体内抗肿瘤活性反映了小鼠宿主免疫细胞功能的调节。首先,rmmc -4550不能抑制免疫功能低下的rag -2缺陷小鼠的肿瘤生长。其次,当CD8+ t细胞在免疫功能正常的小鼠中被耗尽时,其疗效显著减弱,这表明CD8+ t细胞对肿瘤生长抑制很重要。第三,Shp2抑制与抗ctla4或抗pd - l1治疗联合具有加性活性,导致部分小鼠肿瘤完全消退。再挑战研究也证明了联合治疗引起的免疫记忆的存在。检查点阻断的附加活性表明,除了抑制检查点信号外,还有另一种作用机制。第四,对肿瘤微环境中的免疫景观的分析确实揭示了适应性和先天免疫机制的调节。与检查点阻断类似,RMC-4550增加了肿瘤中CD8+ t细胞浸润的频率,相应降低了PD-1的表达。此外,Shp2抑制通过显著增加M1和降低M2来显著改变极化巨噬细胞群,这是抗ctla4或抗pd - l1所没有的效果。总的来说,这些结果表明SHP2抑制与检查点阻断不同,代表了一种新的研究策略,可以同时利用两种抗肿瘤机制:直接抑制癌细胞生长和调节肿瘤微环境。含有对SHP2敏感的致癌驱动突变和对检查点抑制剂具有临床敏感性的肿瘤可能特别感兴趣。引文格式:Elsa Quintana, Kasia Mordec, Robert J. Nichols, David Wildes, Chris J. Schulze, Darienne R. Myers, Mallika Singh, Elena Koltun, Adrian Gill, Stephen Kelsey, Mark A Goldsmith, Jan A.M.史密斯。SHP2的变构抑制通过调节先天和适应性机制诱导pd -1敏感肿瘤的抗肿瘤免疫[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志,2019;7(2增刊):摘要nr A103。
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Abstract A103: Allosteric inhibition of SHP2 induces antitumor immunity in PD-1-sensitive tumors through modulation of both innate and adaptive mechanisms
The protein-tyrosine phosphatase SHP2, encoded by PTPN11, is a known oncogenic driver in a subset of cancers and a central signaling node in the RTK-RAS-MAPK pathway. Genetic and pharmacologic evidence supports a role for SHP2 in driving the proliferation of cancer cells dependent upon a range of activated RTKs, certain RAS and BRAF mutations, and NF1 loss of function mutations. In contrast, a role for SHP2 in antitumor immunity is not well established. SHP2 binds to phosphorylated ITIM and ITAM domains on regulatory receptors in immune cells and multiple reports have demonstrated a SHP2/PD-1 physical interaction. Recently it has been proposed that SHP2 transduces the PD-1 inhibitory checkpoint signal by direct de-phosphorylation of CD28. In this study we show that a peptide comprising two tyrosine phosphorylated 9-mers sequences from the PD-1 ITAM (connected by a PEG8 linker) can activate purified SHP2 enzyme. We also demonstrate that, like checkpoint inhibitors, allosteric inhibition of SHP2 activates NFAT-mediated gene expression in a reporter gene PD-1/PD-L1 bioassay. Based on these findings, we evaluated the impact of SHP2 inhibition on murine host immune cells and the tumor immune microenvironment in vivo using RMC-4550, a novel small-molecule allosteric inhibitor of SHP2. Oral daily administration of RMC-4550 significantly inhibited tumor growth in three syngeneic tumor models sensitive to checkpoint blockade. The inhibitory activity was comparable, and in some cases superior, to checkpoint inhibition. RMC-4550 did not inhibit growth in any of these cancer cell lines in vitro, suggesting that activity was not due to a tumor cell intrinsic antiproliferative effect. Rather, antitumor activity in vivo reflected modulation of murine host immune cell function. First, RMC-4550 did not inhibit tumor growth in immunocompromised Rag-2-deficient mice. Second, efficacy was significantly attenuated when CD8+T-cells were depleted in immunocompetent mice, suggesting that CD8+T-cells were important for tumor growth inhibition. Third, Shp2 inhibition had additive activity in combination with anti-CTLA4 or anti-PD-L1 treatment, resulting in complete tumor regression in some mice. Rechallenge studies also demonstrated the presence of immunologic memory induced by combination therapy. The additive activity with checkpoint blockade suggests an additional mechanism of action beyond inhibition of the checkpoint signal. Fourth, analysis of the immune landscape in the tumor microenvironment indeed revealed modulation of both adaptive and innate immune mechanisms. Similar to checkpoint blockade, RMC-4550 increased the frequency of CD8+T-cell infiltrates in tumors with a corresponding decrease in their PD-1 expression. In addition, Shp2 inhibition significantly shifted polarized macrophage populations by markedly increasing M1 and decreasing M2, effects not seen with anti-CTLA4 or anti-PD-L1. Collectively, these results suggest that SHP2 inhibition is not identical to that of checkpoint blockade and represents a novel investigational strategy that could leverage two antitumor mechanisms simultaneously: direct inhibition of cancer cell growth and modulation of the tumor microenvironment. Tumors that harbor oncogenic driver mutations sensitive to SHP2 and with established clinical sensitivity to checkpoint inhibitors could be of particular interest. Citation Format: Elsa Quintana, Kasia Mordec, Robert J. Nichols, David Wildes, Chris J. Schulze, Darienne R. Myers, Mallika Singh, Elena Koltun, Adrian Gill, Stephen Kelsey, Mark A Goldsmith, Jan A.M. Smith. Allosteric inhibition of SHP2 induces antitumor immunity in PD-1-sensitive tumors through modulation of both innate and adaptive mechanisms [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A103.
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