The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein lymphoid tyrosine phosphatase) is present in 5–10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its proautoimmune allele have in tumor immunity is poorly defined. To interrogate the role this allele may have in the antitumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of lymphoid tyrosine phosphatase, PEST domain–enriched protein (PEP), is mutated at position 619 to produce the relevant proautoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wild-type mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cells and CD4 T cells. In addition, there are more conventional dendritic cell type 1 (cDC1) cells and fewer myeloid-derived suppressor cells in tumors from PEP-619WW mice. Interestingly, the tumor-infiltrating PEP-619WW cDC1 cells have decreased PD-L1 expression compared with cDC1 cells from PEP-wild-type mice. Taken together, our data show that the proautoimmune allele of Ptpn22 drives a strong antitumor response in innate and adaptive immune cells resulting in superior control of tumors.

酪氨酸磷酸酶PTPN22的 1858C>T 等位基因（导致编码的蛋白质淋巴酪氨酸磷酸酶中的氨基酸取代 R620W）存在于 5-10% 的北美人群中，并且与许多自身免疫性疾病密切相关。尽管已经进行了大量研究来定义该等位基因如何增强自身免疫，但影响PTPN22及其在肿瘤免疫中的自身免疫等位基因尚不明确。为了探究该等位基因在抗肿瘤免疫反应中可能发挥的作用，我们使用 CRISPR/Cas9 生成小鼠，其中淋巴酪氨酸磷酸酶的直系同源物 PEST 域富集蛋白 (PEP) 在 619 位发生突变以产生相关的自身免疫原突变（R619W）。这项研究的结果表明，与野生型小鼠相比，这种改变的纯合子小鼠 (PEP-619WW) 能够抵抗肿瘤生长。与这些结果一致，来自 PEP-619WW 小鼠的肿瘤具有更多的 CD45 浸润物，其中含有更多的活化 CD8 T 细胞和 CD4 T 细胞。此外，PEP-619WW 小鼠的肿瘤中有更多的常规树突状细胞 1 型 (cDC1) 细胞和更少的髓源性抑制细胞。有趣的是，与来自 PEP-野生型小鼠的 cDC1 细胞相比，肿瘤浸润性 PEP-619WW cDC1 细胞的 PD-L1 表达降低。总之，我们的数据表明，自身免疫原等位基因Ptpn22在先天性和适应性免疫细胞中驱动强烈的抗肿瘤反应，从而对肿瘤进行更好的控制。