The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4-positive T cells that are PD-1-negative
The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4-positive T cells that are PD-1-negative
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DOI：
10.1182/blood.2019002206
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发表时间：
2019-12-05
期刊：
影响因子：
20.3
通讯作者：
Rodig, Scott J.
中科院分区：
文献类型：
--
作者：
Patel, Sanjay S.;Weirather, Jason L.;Rodig, Scott J.
经典霍奇金淋巴瘤（cHL）是一种罕见的、非典型的、生发中心来源的B细胞（霍奇金Reed-Sternberg [HRS]细胞）嵌入强健但无效的炎症环境中的肿瘤。cHL肿瘤微环境（TME）被划分为富含程序性细胞死亡-1配体（PD-L1）阳性HRS细胞和肿瘤相关巨噬细胞（tam）的“小生境”，它们与PD-1阳性T细胞结合，通过PD-L1/PD-1信号传导抑制抗肿瘤免疫。尽管cHL对PD-1检查点阻断非常敏感，但大多数患者最终会复发，需要其他治疗方案。使用多重免疫荧光显微镜和数字图像分析，我们发现cHL高度富集非T调节性、细胞毒性T淋巴细胞相关蛋白4 （CTLA-4）阳性T细胞（与反应性淋巴组织相比），其数量超过pd -1阳性和淋巴细胞活化基因3 （LAG-3）阳性T细胞。此外，T细胞接触HRS细胞时，CTLA-4比PD-1或LAG-3更常呈阳性。我们进一步发现，HRS细胞和tam的一个子集对CTLA-4配体CD86呈阳性，并且在75 pm HRS细胞生态位内，CTLA-4阳性和CD86阳性的T细胞和tam的比例相对于该区域以外的区域更大（ctla - 4,38 %对18% [P = 0.0001]; CD86, 38%对24% [P = 0.0007]）。重要的是，在各种治疗（包括PD-1阻断）后复发的cHL肿瘤中，ctla -4阳性细胞存在，并局部接触HRS细胞。这些结果暗示CTLA-4:CD86相互作用是HRS细胞周围免疫特权生态位的一个组成部分，并提出了PD-1阻断难治性cHL患者可能受益于CT-4阻断的可能性。
Classic Hodgkin lymphoma (cHL) is a tumor composed of rare, atypical, germinal center-derived B cells (Hodgkin Reed-Sternberg [HRS] cells) embedded within a robust but ineffective inflammatory milieu. The cHL tumor microenvironment (TME) is compartmentalized into "niches" rich in programmed cell death-1 ligand (PD-L1)-positive HRS cells and tumor-associated macrophages (TAMs), which associate with PD-1-positive T cells to suppress antitumor immunity via PD-L1/PD-1 signaling. Despite the exquisite sensitivity of cHL to PD-1 checkpoint blockade, most patients eventually relapse and need therapeutic alternatives. Using multiplex immunofluorescence microscopy with digital image analysis, we found that cHL is highly enriched for non-T-regulatory, cytotoxic T-Iymphocytea-ssociated protein 4 (CTLA-4)-positive T cells (compared with reactive lymphoid tissues) that outnumber PD-1-positive and lymphocyte-activating gene-3 (LAG-3)-positive T cells. In addition, T cells touching HRS cells are more frequently positive for CTLA-4 than for PD-1 or LAG-3. We further found that HRS cells, and a subset of TAMs, are positive for the CTLA-4 ligand CD86 and that the fractions of T cells and TAMs that are CTLA-4-positive and CD86-positive, respectively, are greater within a 75 p.m HRS cell niche relative to areas outside this region (CTLA-4, 38% vs 18% [P = .0001]; CD86, 38% vs 24% [P = .0007]). Importantly, CTLA-4-positive cells are present, and focally contact HRS cells, in recurrent cHL tumors following a variety of therapies, including PD-1 blockade. These results implicate CTLA-4:CD86 interactions as a component of the immunologically privileged niche surrounding HRS cells and raise the possibility that patients with cHL refractory to PD-1 blockade may benefit from CT-4 blockade.