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

Castenmiller, Suzanne M.; Groot, R de; Guislain, Aurélie; Monkhorst, Kim; Hartemink, Koen J.; Veenhof, A. A. F. A.; Smit, Egbert F.; Haanen, John B.A.G.; Wolkers, Monika C.

doi:10.1016/j.iotech.2022.100090

Cited by 3 publications

(6 citation statements)

References 65 publications

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“…Additionally, we and others showed that TIL products generated from treatment-naïve non-small cell lung cancer (NSCLC)-patients contain poly-functional tumor-reactive T cell products 12,13 . As for melanoma alike 7,8 , we found that tumor-reactive T cells were also present in TIL products from late-stage pretreated NSCLC patients, indicating that TIL therapy could potentially be broadly applicable to NSCLC patients 14 . In line with these findings, a first very promising phase I clinical trial with TIL therapy in PD1-refractory patients recently reported a reduced tumor burden in most patients 15 .…”

Section: Introductionmentioning

confidence: 74%

“…Successful TIL therapy requires sufficient expansion to achieve a clinical response 2 . To define whether the cellular composition of the tumor digest correlated with the capacity of TILs to expand in vitro , we used TIL expansion data we previously reported 12,14 , and complemented them with the analysis for tumors from newly recruited patients (table 1). We observed no overt correlations of the percentage of immune infiltrates with the fold expansion rate during the pre-REP (first 10-13 days of expansion) and the REP phase (second 10-13 days of expansion), except from a slight negative correlation of conventional CD4 + T cells with TIL expansion during the pre-REP phase (r s =-0.35, p=0.031; figure 2C,D).…”

Section: Resultsmentioning

confidence: 99%

“…Four early-stage patients were excluded from the downstream analysis due to technical errors, resulting in a cohort of 26 early-stage NSCLC patients and 20 late-stage NSCLC patients. 11 early-stage and 18 late-stage patients had been included in previous reports 12,14 (table 1). Sex was not considered as a biological variable.…”

Section: Methodsmentioning

confidence: 99%

“…All samples were weighed prior to digestion. Tissue digestion was performed as previously described 12,14 . Briefly, freshly isolated tumor or lung tissue was finely chopped and enzymatically digested for 45 min at 37°C with RPMI (Gibco) containing 30 IU/ml collagenase IV (Worthington), 12,5 μg/ml DNAse (Roche), and 1% FBS (Bodego, Bodinco BV) to obtain a single cell suspension.…”

Section: Methodsmentioning

confidence: 99%

“…Staining protocols for freshly digested tumor material or expanded TILs was previously described 12,14 . For detailed information about antibodies, see table 2.…”

Section: Flow Cytometry Acquisition and Analysismentioning

confidence: 99%

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Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Castenmiller,

Kanagasabesan,

Guislain

et al. 2024

Preprint

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Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has shown great potential for the treatment of solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy, and the parameters that define the likelihood of TIL products to be tumor reactive are to date unknown. Defining prognostic markers that correlate with high level of tumor-reactivity is key for achieving better tailored immunotherapies.To determine whether the composition of immune cell infiltrates correlates with the tumor-reactivity of expanded TIL products, we employed multi-parameter flow cytometry to characterize the immune cell infiltrates from 26 early-stage, and 20 late-stage NSCLC tumor lesions. Unbiased flow cytometry analysis with Cytotree and Spearman’s Rank Correlation was used to correlate immune infiltrates with the expansion rate, immune cell activation and T cell differentiation state, and the anti-tumor response of TIL products generated from the same lesions.The composition of tumor immune infiltrates was highly variable between patients, irrespective of the disease stage. High percentages of B cell infiltrates positively correlated with the presence of conventional CD4+T cells, and an overall increase of naïve T cell infiltrates. In contrast, high B cell infiltrates negatively correlated with the tumor-reactivity of expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. Tumors with high B cell infiltrates contained IgD+BCL6+B cells and CXCR5+BLC6+CD4+T cell infiltrates and an increased percentage of naïve CD8+T cells, indicative of the presence of tertiary lymphoid structures (TLS) in tumors with high B cell infiltrates.This study reveals that the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of expanded TIL products from NSCLC tumor lesions. Importantly, the tumor-responsiveness of TIL products negatively correlated with the presence of TLS-associated immune infiltrates in tumors. Our finding may thus help improve patient selection for TIL therapy.

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Section: Introductionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Staining protocols for freshly digested tumor material or expanded TILs was previously described 12,14 . For detailed information about antibodies, see table 2.…”

Section: Flow Cytometry Acquisition and Analysismentioning

confidence: 99%

See 3 more Smart Citations

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Castenmiller,

Kanagasabesan,

Guislain

et al. 2024

Preprint

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Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies

Wu,

Valenca-Pereira,

Cendali

et al. 2024

Nat Commun

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Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.

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Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Castenmiller,

Kanagasabesan,

Guislain

et al. 2024

OncoImmunology

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

Cited by 3 publications

References 65 publications

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies

Tertiary lymphoid structure-related immune infiltrates in NSCLC tumor lesions correlate with low tumor-reactivity of TIL products

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