 On the cover: In this issue, Wu et al. investigate the role of dendritic cells (DCs) within the tumor immune microenvironment and their impact on immunotherapy outcomes in patients. Using data from clinical trials and mouse models, they identify a specific functional DC state characterized by CCL19 expression that can augment the antitumor activity of CD8+ T cells and is associated with favorable immunotherapy responses. Intratumoral and circulating CCL19 levels may be used as a marker to predict immunotherapy efficacy. On the cover, DCs (in pink) within the tumor microenvironment produce CCL19, which acts on CD8+ T cells (in blue) to enhance their antitumor effectiveness. Cover art: Sonhita Chakrabarty. 對此，西班牙應用醫(yī)學研究中心、納瓦拉健康研究所、西班牙癌癥網(wǎng)絡生物醫(yī)學研究中心發(fā)表觀點文章：樹突狀細胞——三陰性乳腺癌抗腫瘤CD8陽性T淋巴細胞的獵頭。“獵頭”二字形象地反映了樹突狀細胞對殺手型T淋巴細胞的作用。 樹突狀細胞和抗原交叉啟動已被證實對于建立和維持抗癌免疫至關重要，這反過來又在許多臨床前環(huán)境中促進了免疫檢查點抑制劑的有效性。與臨床前結果一致，在許多癌癥類型中，樹突狀細胞浸潤、CD8陽性T淋巴細胞免疫浸潤與良好的整體臨床療效始終相關。復旦研究表明，在三陰性乳腺癌中，顯示獲得性成熟特征的樹突狀細胞，與免疫檢查點PD-(L)1抑制劑的良好療效密切相關。重要的是，研究者證明三陰性乳腺癌微環(huán)境成熟樹突狀細胞可產生高水平的趨化因子CCL19。事實上，利用來自三陰性乳腺癌患者免疫檢查點抑制劑治療的若干臨床試驗數(shù)據(jù)，研究者證實僅CCL19表達就可確定對PD-(L)1抑制劑療效良好者。 CCL19與其姊妹趨化因子CCL21類似，通過CCR7受體發(fā)揮作用，該受體表達于多種免疫細胞群，例如幼稚和中央記憶型T淋巴細胞或成熟樹突狀細胞，除其他功能外，還介導T淋巴細胞在毛細血管后微靜脈中聚集進入次級淋巴器官或淋巴結內T淋巴細胞區(qū)的組織。研究者還證實，CCL19陽性樹突狀細胞與腫瘤內的三級淋巴結構密切相關，表明樹突狀細胞通過調控免疫微環(huán)境空間分布以激活抗腫瘤免疫的潛在作用。這類免疫樞紐（T淋巴細胞、樹突狀細胞聚集體和三級淋巴結構）存在于腫瘤微環(huán)境內或附近以及毛細血管后微靜脈（也可以是有組織三級淋巴結構的一部分）已被證明與免疫檢查點抑制劑臨床療效良好以及對PD-1抑制劑有效的T淋巴細胞群聚集密切相關。  Med. 2023 Jun 9;4(6):341-343. Impact Score: 20.28 Dendritic cells, headhunters for anti-tumor CD8+ T cells in triple-negative breast cancer. Carlos Luri-Rey, Almudena Manzanal, Beatrice Pinci, Alvaro Teijeira. Center for Applied Medical Research (CIMA), Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. How do we identify patients most likely to benefit from immune checkpoint blockade therapies? This month in Med, Wu and colleagues identify that CCL19+ mature dendritic cells correlated with responses to anti-PD-(L)1 immunotherapy in triple-negative breast cancer patients, suggesting the use of CCL19 as a biomarker to predict patient outcomes. Dendritic cells (DCs) and antigen cross-priming have been shown to be essential to set up and sustain anti-cancer immunity, which in turn promotes the effectiveness of checkpoint immune blockade therapy in a number of preclinical settings. In line with preclinical results, DC infiltration consistently correlates with CD8+ T cell immune infiltration and good overall clinical response in many cancer types. Wu and colleagues show that in triple-negative breast cancer (TNBC), the presence of DCs showing features of acquired maturation strongly correlates with a good response to anti-PD-(L)1-based immune checkpoint blockade. Importantly, they demonstrate that mature DCs in the TNBC microenvironment produce high levels of the chemokine CCL19. In fact, using data from several clinical trials of patients with TNBC treated with immune checkpoint therapies, the authors show that CCL19 expression alone can identify good responders to PD-(L)1 blockade. CCL19 (similarly to its sister chemokine CCL21) acts through the CCR7 receptor expressed in several immune cell populations, such as naive and central memory T cells or mature DCs, and mediates, among other functions, the recruitment of T cells across high endothelial venules (HEVs) into secondary lymphoid organs (SLOs) or the organization of the T cell zone within the lymph nodes. The authors were also able to show that the presence of CCL19+ DCs correlated with organized lymphoid aggregates in the tumor microenvironment (TME), including bona fide tertiary lymphoid structures (TLSs), suggesting a potential role for DCs in organizing immune cell microenvironments to sustain anti-tumor immune responses. Both the presence of these types of immune hubs (T cell-DC aggregates and TLSs) within or next to the TME and the presence of HEVs (that can also be part of organized TLSs) have been shown to strongly correlate with good clinical response to immune checkpoint blockade-based therapies and with the recruitment of the T cell populations that are known to respond to PD-1 blockade (Tpex). Therefore, the results of Wu and coworkers emphasize the key importance of DCs in the TME not only to prime anti-tumor T cells but also to recruit the most important anti-tumor immune populations and organize effective immune responses that require a specific spatial organization to maximize the immune cell interactions that are needed to elicit efficient anti-tumor immunity. Despite all the correlative data suggesting the key importance of this type of tissue organization, it is still unclear what the crucial event is that allows the generation of such immune cell hubs and whether the formation of these immune cell microenvironments in the tumors is guided by the same mechanisms that govern SLO formation. The fact that CCL19+ DC infiltration in tissue correlates with these immune cell hubs does not clarify which cells are initially needed to organize these tissue immune environments and whether they themselves can direct such tissue organization. This information will be of great relevance for the design of novel therapeutic approaches to maximize tumor sensitivity to immune checkpoint blockade. In this manuscript, the authors provide proof that CCL19 injection alone or the co-engraftment of DCs expressing CCL19 is sufficient to enhance sensitivity to immune checkpoint blockade in at least two mouse models of TNBC, suggesting that DCs may be very important in the organization of these anti-tumor immune territories or that these immune territories are exerting their anti-tumor functions by recruiting DCs into the TME. The DC population identified here shows a strong similarity with already described mature dendritic cells enriched in immunoregulatory molecules (mregDCs) in other tumor types. Defining whether immunomodulatory molecules expressed by the infiltrating mature DCs could also be amenable to intervention to further potentiate their functions will be an important step toward the design of new therapeutic interventions. Another important question that remains to be answered is whether approaches aiming to expand, recruit, and promote the maturation of DCs in the TME will render tumors amenable to immune checkpoint therapy. Preclinical experiments pursuing DC expansion, such as Flt3L treatment, have been very promising, but the clinical development of such approaches is still in its early phases. Intratumoral vaccination with DCs has also been assayed, and a few preclinical studies have attempted to specifically enhance recruitment of DCs to the tumor site. Whether having enough and fully activated DCs in the TME is sufficient to promote immunity in poorly immunogenic tumors is a question that still needs to be addressed. In order to design new therapeutic approaches, it is very important to determine the essential immune functions elicited by DCs in the TME (Figure 1). Cross-priming seems to be an absolute requirement for anti-tumor CD8+ T cell responses, at least in preclinical models. In this study, Wu et al. show that recruitment of CCR7+ T cells is likely a fundamental mechanism behind DC activity in tumors and that intratumoral CCL19 injection itself can render tumors sensitive to anti-PD-1 treatment. The importance of DCs, particularly cDC1s, in promoting immune infiltration has been suggested before. Active interaction of DCs within the tumor with T cells has been well characterized by intravital microscopy and in human cancer specimens. Nonetheless, the nature of the stimuli provided in this dialogue has not yet been completely defined. Strategies to circumvent these functions, such as vaccination strategies, intratumoral delivery of adoptive T cell therapies, or therapeutic proteins, may be important alternatives, especially because of the extensively reported paucity of DCs in cancer patients. The work of Wu and colleagues provides several important findings that are crucial for understanding the essential role of DCs in cancer immunity: first, by identifying their importance in a less well-explored cancer type, TNBC, and second, by highlighting the importance of DCs in the recruitment of the CD8+ T cells that will be most effective in tumor elimination when treating patients with checkpoint blockade. In the future, it will be important to understand whether therapies promoting DC infiltration and function will expand the number of patients that can benefit from immune checkpoint blockade, particularly if this might include those patients with small chances of benefitting from immunotherapy, such as those with a low antigenic cargo in their tumors. DOI: 10.1016/j.medj.2023.05.004 |
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