Tertiary Lymphoid Structure-Associated B Cells Enhance CXCL13(+)CD103(+)CD8(+) Tissue-Resident Memory T-Cell Response to Programmed Cell Death Protein 1 Blockade in Cancer Immunotherapy.

Although the presence of tertiary lymphoid structures (TLS) correlates with positive responses to immunotherapy in many solid malignancies, the mechanism by which TLS enhances antitumor immunity is not well understood. The present study aimed to investigate the underlying cross talk circuits between B cells and tissue-resident memory T (Trm) cells within the TLS and to understand their role in the context of immunotherapy. Immunostaining and H&E staining of TLS and chemokine (C-X-C motif) ligand 13 (CXCL13)+ cluster of differentiation (CD)103+CD8+ Trm cells were performed on tumor sections from patients with gastric cancer (GC). The mechanism of communication between B cells and CXCL13+CD103+CD8+ Trm cells was determined in vitro and in vivo. The effect of CXCL13+CD103+CD8+ Trm cells in suppressing tumor growth was evaluated through anti-programmed cell death protein (PD)-1 therapy. The presence of TLS and CXCL13+CD103+CD8+ Trm cells in tumor tissues favored a superior response to anti-PD-1 therapy in patients with GC. Additionally, our research identified that activated B cells enhanced CXCL13 and granzyme B secretion by CD103+CD8+ Trm cells. Mechanistically, B cells facilitated the glycolysis of CD103+CD8+ Trm cells through the lymphotoxin-α/tumor necrosis factor receptor 2 (TNFR2) axis, and the mechanistic target of rapamycin signaling pathway played a critical role in CD103+CD8+ Trm cells glycolysis during this process. Moreover, the presence of TLS and CXCL13+CD103+CD8+ Trm cells correlated with potent responsiveness to anti-PD-1 therapy in a TNFR2-dependent manner. This study further reveals a crucial role for cellular communication between TLS-associated B cell and CXCL13+CD103+CD8+ Trm cells in antitumor immunity, providing valuable insights into the potential use of the lymphotoxin-α/TNFR2 axis within CXCL13+CD103+CD8+ Trm cells for advancing immunotherapy strategies in GC.

Hu C ，You W ，Kong D ，Huang Y ，Lu J ，Zhao M ，Jin Y ，Peng R ，Hua D ，Kuang DM ，Chen Y ... -  《-》

Tertiary lymphoid structures show infiltration of effective tumor-resident T cells in gastric cancer.

Several studies have reported that tissue-resident memory T cells (TRM cells) or tertiary lymphoid structures (TLSs) are associated with a good prognosis. The aim of this study was to clarify the association of TRM cells and TLSs in the tumor immune microenvironment in gastric cancer (GC). We performed immunohistochemical and immunofluorescence staining to detect the presence of CD103+ T cells and to assess the association between CD103+ T cells and TLSs. CD103+ T cells were observed in the tumor epithelium accompanied by CD8+ T cells and were associated with a better prognosis in GC. Furthermore, CD103+ T cells were located around TLSs, and patients with CD103high had more rich TLSs. Patients who had both CD103high cells and who were TLS-rich had a better prognosis than patients with CD103low cells and who were TLS-poor. Moreover, for patients who received PD-1 blockade therapy, CD103high and TLS-rich predicted a good response. Flow cytometry was performed to confirm the characteristics of CD103+ CD8+ T cells and showed that CD103+ CD8+ T cells in GC expressed higher levels of PD-1, granzyme B, and interferon-γ than CD103- CD8+ T cells. Our results suggested that CD103+ CD8+ cells in GC are correlated with TLSs, resulting in enhanced antitumor immunity in GC.

Mori T ，Tanaka H ，Suzuki S ，Deguchi S ，Yamakoshi Y ，Yoshii M ，Miki Y ，Tamura T ，Toyokawa T ，Lee S ，Muguruma K ，Wanibuchi H ，Ohira M ... -  《-》

Functional Heterogeneity of CD4(+) Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC.

Oja AE ，Piet B ，van der Zwan D ，Blaauwgeers H ，Mensink M ，de Kivit S ，Borst J ，Nolte MA ，van Lier RAW ，Stark R ，Hombrink P ... -  《Frontiers in Immunology》

CD103(+)CD8(+) T(RM) Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17.

Accumulation of CD103+CD8+ resident memory T (TRM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of TRM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103+CD8+ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103+CD8+ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103+CD8+ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103+CD8+ tumor TRM, but not CD103-CD8+ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103+CD8+ TRM are associated with better outcomes in anti-PD-(L)1-treated patients.

Corgnac S ，Malenica I ，Mezquita L ，Auclin E ，Voilin E ，Kacher J ，Halse H ，Grynszpan L ，Signolle N ，Dayris T ，Leclerc M ，Droin N ，de Montpréville V ，Mercier O ，Validire P ，Scoazec JY ，Massard C ，Chouaib S ，Planchard D ，Adam J ，Besse B ，Mami-Chouaib F ... -  《-》

Intratumoral CXCL13(+) CD160(+) CD8(+) T cells promote the formation of tertiary lymphoid structures to enhance the efficacy of immunotherapy in advanced gastric cancer.

Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen. We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13+ CD160+ CD8+ T cells and TLSs. The relationship between CXCL13+ CD160+ CD8+ T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13+ CD160+ CD8+ T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry. We found that responders exhibited higher levels of TLSs and CXCL13+ CD160+ CD8+ T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13+ CD160+ CD8+ T cells in surgical resections. Moreover, we discovered that vitamin B6 in CD160+ CD8+ T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5+ B cells and the formation of TLSs. The number and maturity of TLSs, along with the extent of CXCL13+ CD160+ CD8+ T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B6 could enhance the secretion of CXCL13 by CD160+ CD8+ T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer.

Wang J ，Liang Y ，Xue A ，Xiao J ，Zhao X ，Cao S ，Li P ，Dong J ，Li Y ，Xu Z ，Yang L ... -  《Journal for ImmunoTherapy of Cancer》