Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity.
Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity.
复制标题
DOI：
10.3390/cancers13050953
复制
发表时间：
2021-02-25
期刊：
影响因子：
5.2
通讯作者：
Oghumu S
中科院分区：
文献类型：
--
作者：
Anderson K;Ryan N;Alkhimovitch A;Siddiqui A;Oghumu S
免疫原性差的头颈部鳞状细胞癌（HNSCC）由于对免疫疗法的应答率低而难以治疗。抑制PI 3 K催化亚基p110γ（在白细胞和一些HNSCC中表达）已显示出治疗HNSCC的前景;正在进行临床试验以评估其有效性。然而，在免疫原性差的HNSCC中，PI 3 K p110γ抑制对宿主免疫系统的影响尚未完全描述。在这项研究中，我们的研究小组使用MOC 2细胞系的原位小鼠模型，表征了在不存在PI 3 K p110γ的情况下对免疫原性较差的HNSCC的免疫反应。我们发现缺乏p110γ的小鼠没有表现出显著不同的肿瘤生长或转移，尽管我们观察到原发肿瘤部位的抗肿瘤和免疫抑制活性显著升高。我们的研究结果表明，如果与检查点抑制剂一起给药，PI 3 K p110γ抑制可能会增强针对免疫原性差的HNSCC的抗肿瘤免疫力。HNSCC是第六常见的癌症，每年约有650，000例新发病例。在HNSCC中，PI 3 K途径中的功能突变的获得是常见的，并且PI 3 K p110γ亚基的抑制在HNSCC治疗中显示出希望。然而，鉴于PI 3 K p110γ在骨髓和淋巴免疫细胞功能中起重要作用，因此了解PI 3 K p110γ抑制如何影响独立于肿瘤细胞的抗肿瘤免疫应答至关重要。为了阐明PI 3 K p110γ在HNSCC中的功能，我们采用了一种原位小鼠模型，在Pik 3cg −/−小鼠上使用免疫原性和侵袭性较差的细胞系MOC 2。我们观察到野生型和Pik 3cg −/−小鼠在肿瘤注射后20天后显示出相似的HNSCC肿瘤生长和转移率。野生型和Pik 3cg −/−小鼠对MOC 2口腔肿瘤的T细胞浸润和内在T细胞反应相当。有趣的是，与携带肿瘤的野生型小鼠相比，携带肿瘤的Pik 3cg −/−小鼠的免疫应答通过T细胞的抗肿瘤细胞毒性分子（IFN-γ，IL-17）以及骨髓细胞和T细胞的免疫检查点标记物（PD-L1，PD-1）表达增加来标记。综上所述，我们的研究结果表明，抑制PI 3 K p110γ调节肿瘤相关免疫细胞，当与选择性检查点抑制剂联合使用时，这可能增强HNSCC治疗。
Poorly immunogenic head and neck squamous carcinomas (HNSCC) remain difficult to treat due to poor response rates to immunotherapy. Inhibition of the PI3K catalytic subunit p110γ, which is expressed in leukocytes and some HNSCCs, has shown promise in treating HNSCC; with clinical trials underway to gauge its effectiveness. However, the effect of PI3K p110γ inhibition on the host immune system in poorly immunogenic HNSCC has not been fully described. In this study, our group characterized the immune response to poorly immunogenic HNSCC in the absence of PI3K p110γ using an orthotopic mouse model with the MOC2 cell line. We found that mice lacking p110γ did not demonstrate significantly different tumor growth or metastasis, though we observed substantial elevation in both anti-tumor and immunosuppressive activity at the primary tumor site. Our results indicate that PI3K p110γ inhibition may potentially enhance anti-tumor immunity against poorly immunogenic HNSCC if administered with checkpoint inhibitors. HNSCC is the sixth most common cancer, with around 650,000 new cases yearly. Gain of function mutations in the PI3K pathway are common in HNSCC, and inhibition of the PI3K p110γ subunit has shown promise in HNSCC treatment. However, given that PI3K p110γ plays an important role in myeloid and lymphoid immune cell function, it is essential to understand how PI3K p110γ inhibition affects the anti-tumor immune response independent of tumor cells. To elucidate PI3K p110γ function in HNSCC, we employed an orthotopic mouse model using poorly immunogenic and aggressive cell line MOC2 on Pik3cg−/− mice. We observed that wild-type and Pik3cg−/− mice displayed similar rates of HNSCC tumor growth and metastasis after 20 days following tumor injection. T-cell infiltration and intrinsic T-cell responses to MOC2 oral tumors were comparable between wild-type and Pik3cg−/− mice. Interestingly, the immune response of tumor-bearing Pik3cg−/− mice was marked by increased anti-tumor cytotoxic molecules (IFN-γ, IL-17)) by T-cells and immune checkpoint marker (PD-L1, PD-1) expression by myeloid cells and T-cells compared to tumor-bearing wild-type mice. Taken together, our findings demonstrate that inhibition of PI3K p110γ modulates tumor-associated immune cells, which likely potentiates HNSCC treatment when used in combination with selective checkpoint inhibitors.
登录
查看更多内容
影响因子：
2.3
作者：
El Jamal SM;Taylor EB;Abd Elmageed ZY;Alamodi AA;Selimovic D;Alkhateeb A;Hannig M;Hassan SY;Santourlidis S;Friedlander PL;Haikel Y;Vijaykumar S;Kandil E;Hassan M
通讯作者：
Hassan M
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
DOI：
10.1073/pnas.1110339109
发表时间：
2012-01-24
影响因子：
11.1
作者：
Cummings, Hannah E.;Barbi, Joseph;Satoskar, Abhay R.
通讯作者：
Satoskar, Abhay R.
影响因子：
8.8
作者：
Janku F;Hong DS;Fu S;Piha-Paul SA;Naing A;Falchook GS;Tsimberidou AM;Stepanek VM;Moulder SL;Lee JJ;Luthra R;Zinner RG;Broaddus RR;Wheler JJ;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
7.3
作者：
Anderson, Kelvin;Ryan, Nathan;Oghumu, Steve
通讯作者：
Oghumu, Steve