Biology subjects

Haanen, J. B. A. G.

Publications and source records attributed to Haanen, J. B. A. G..

4 recordsLinked to original sources

bioRxiv2026

PAIR-Scan: Single-step identification of highly potent TCR-neoantigen pairs through library-on-library screening

Tumors contain a mixture of T cells with bystander reactivities and reactivities towards different, frequently patient-specific, cancer (neo)antigens. The one-step identification of highly active TCR-antigen pairs in human tumors would be valuable, both as a monitoring tool and to boost T cell reactivities of interest. Here, we develop PAIR-Scan, an HLA-agnostic library-on-library screening technology that identifies functionally active TCR-neoantigen pairs among tens of thousands of candidate pairs in a single step. We demonstrate the value of PAIR-Scan on a range of tumor samples and for the direct identification of TCR-recognized minimal peptides. In addition, we demonstrate that PAIR-Scan correctly ranks TCRs reactive to the same antigen by their relative tumor-killing efficiency. Together, these data demonstrate the value of PAIR-Scan for both the dissection of T cell responses in clinical samples and to generate large-scale datasets for the development of predictive models of TCR reactivity.

immunology↗

bioRxiv2022

Effective generation of tumor-infiltrating lymphocyte products from metastatic non-small-cell lung cancer (NSCLC) lesions irrespective of location and previous treatments.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Because current treatment regimens show limited success rates, alternative therapeutic approaches are needed. We recently showed that treatment-naive, stage I/II primary NSCLC tumors contain a high percentage of tumor-reactive T cells, and that these tumor-reactive T cells can be effectively expanded and used for the generation of autologous TIL therapy. Whether these promising findings also hold true for metastatic lesions is unknown yet critical for the translation into the clinic. We here studied the lymphocytic composition and the feasibility to generate tumor-responsive TIL products from metastatic NSCLC lesions that were derived from different locations and from patients who had previously received different treatment regimens, or who were treatment naive. The overall numbers and composition of lymphocyte infiltrates from this various metastatic lesions was by and large comparable to that of early-stage primary NSCLC tumors. With the clinically approved TIL expansion protocol, we effectively expanded TILs from metastatic NSCLC lesions to numbers that were compatible with TIL transfusion, irrespective of the location of the metastasis and of the previous treatment. Importantly, 16 of 21 (76%) tested TIL products displayed anti-tumoral activity, as determined by their production of the key pro-inflammatory cytokines IFN-{gamma}, TNF, IL-2 and of CD137 expression upon incubation with autologous tumor digests by CD8+ and CD4+ T cells. In summary, metastatic NSCLC lesions constitute a viable source for the generation of tumor-reactive TIL products for therapeutic purposes irrespective of their location and the pretreatment regimens.

cancer biology↗

bioRxiv2021

OX40 agonism enhances efficacy of PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Immune checkpoint therapy (ICT) has the potency to eradicate cancer but the mechanisms that determine effective versus non-effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling we examined whether T cell states in the blood circulation could predict responsiveness to a combined ICT, sequentially targeting OX40 costimulatory and PD-1 inhibitory pathways, which effectively eradicated syngeneic mouse tumors. Unbiased assessment of transcriptomic alterations by single-cell RNA sequencing and profiling of cell-surface protein expression by mass cytometry revealed unique activation states for therapy-responsive CD4+ and CD8+ T cells. Effective ICT elicited T cells with dynamic expression of distinct NK cell and chemokine receptors, and these cells were systemically present in lymphoid tissues and in the tumor. Moreover, NK cell receptor-expressing CD8+ T cells were also present in the peripheral blood of immunotherapy-responsive cancer patients. Targeting of the NK cell and chemokine receptors in tumor-bearing mice showed their functional importance for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use of dynamic biomarkers on effector CD4+ and CD8+ T cells to improve cancer immunotherapy.

immunology↗

bioRxiv2020

Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral. blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site. One sentence summaryWe demonstrate that, contrary to CTLA-4 blockade, PD-1 blockade in melanoma patients does not lead to an increase in the breadth or magnitude of the melanoma-reactive CD8 T cell response in peripheral blood, thereby arguing for a dominant effect of PD-1 blockade at the tumor site.

immunology↗