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Stimulation of tumor infiltrating B-cells improves ex-vivo TIL expansion for melanoma sample immunotherapy I

ABSTRACT: Many studies have shown association of tumor infiltrating B-cells and presence of tertiary lymphoid structure with improved clinical responses to immune checkpoint inhibitors therapy. We hypothesized that their presence could also have an impact on TIL therapy response. To address this, we performed RNA-seq of FFPE samples from a cohort of patients that received TIL therapy. Melanoma tumors collected prior to TIL infusion were evaluated for immune content in 9 responders and 11 non-responders to TIL therapy. Our data demonstrate an increase in class-switched memory B-cells in responders compared with non-responders to TIL therapy. In the myeloid compartment, increased presence of dendritic cell populations (pDC, aDC, and iDC) and basophils was observed in responders to TIL therapy, as well as higher content of γδ T cells and effector memory CD8+ T cells (CD8+ Tem) in the T-cell compartment. Next, we assessed the TLS presence in the same cohort by a gene expression signature of 12 chemokines using principal component analysis. The responders showed a higher TLS score compared with the non-responder patients, suggesting that patients responding to TIL therapy had more TLS in their tumors than the non-responder patients. These observations indicate that, same as in the immune checkpoint inhibitors therapy response, presence of B-cells and TLS might have a positive impact in the clinical outcome to TIL therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217387 | GEO | 2024/06/30

REPOSITORIES: GEO

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Project description:Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10-5) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10-6) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.

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Stimulation of tumor infiltrating B-cells improves ex-vivo TIL expansion for melanoma sample immunotherapy I

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