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Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [full scRNAseq]

ABSTRACT: Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222446 | GEO | 2024/02/05

REPOSITORIES: GEO

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Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [scTCRseq]

Project description:Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8+ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

2024-02-05 | GSE222750 | GEO

Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [CD45 scRNAseq]

2024-02-05 | GSE221553 | GEO

Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [bulk RNAseq]

2024-02-05 | GSE221253 | GEO

Tumor-reactive clonotype dynamics dictate clinical response to TIL therapy in melanoma [TCR-Seq]

Project description:Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is effective in cancer patients, yet the profiles, specificity and dynamics of tumor clonotypes remain opaque. Using single-cell RNA/TCR-sequencing, clonotypes were tracked from baseline tumors to ACT products (ACTP) and post-ACT blood and tumor samples from 13 metastatic melanoma patients (NCT03475134). Furthermore, a predictor of tumor-reactive clonotypes was derived from the transcriptomic profiles of tumor-specific or bystander clones. Patients with clinical responses had tumors enriched in tumor-reactive TILs, preferentially expanding in-vitro to generate larger and more tumoricidal products and preferentially re-infiltrating tumors post-ACT. Conversely, lack of responses was associated with tumors devoid of tumor-reactive clonotypes and with cell products mostly composed of blood-borne clonotypes. The exhaustion state characterizing intratumoral tumor-reactive TILs was attenuated during in-vitro expansion and restored after tumor re-engraftment only in responders. Thus, tumor-reactive clonotypes drive clinical response to TIL therapy, providing insight to select patients or improve TILs’ culture.

2023-08-01 | GSE234352 | GEO

Expression data from FACS-sorted CD8+BTLA+ vs CD8+BTLA- Human Tumor-infiltrating Lymphocytes in Metastatic Melanoma

Project description:Adoptive T-cell Therapy (ACT) involves using tumor-infiltrating lymphocytes (TIL) isolated from metastatic melanoma and expanding them ex vivo prior to infusion into lympho-depleted patients. This is one of the most promising approaches to treat metastatic melanoma, with the rates of clinical response between 48-50% based on studies done at NCI, M.D. Anderson Cancer Center (Houston, TX), and Sheba Medical Center (Tel Aviv, Israel). In the Phase II ACT Trial at M.D. Anderson Cancer Center , our group has uncovered an association between positive clinical response and the amount of CD8+ tumor-infiltrating lymphocytes expressing B and T Lymphocyte Attenuator (BTLA), a reported inhibitory receptor on T-cells. We used microarrays to detail the differences in the global programme of gene expression between CD8+BTLA+ vs CD8+BTLA- TILs in order to understand the molecular basis of the clinical association. TILs were isolated by enzymatically digest the melanoma tumor fragments obtained from Stage IIIc/IV melanoma patients at M.D. Anderson Cancer Center. The TILs were expanded with high-dose IL-2 for two weeks prior to sorting by FACS (fluoresecence-activated cell sorter) for CD8+BTLA+ and CD8+BTLA- susbets. RNA was extracted from each sorted subsets and hybridized on Affymetrix microarrays

2013-01-03 | E-GEOD-43260 | biostudies-arrayexpress

Transcriptome profile of Responders and Nonresponders T cells infiltrated lymphocytes (TILs) co-cultured with autologous tumor cells from patients with melanoma.

Project description:Adoptive cell therapy (ACT) based on ex vivo expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate durable antitumor responses even in heavily pretreated patients. However, only a subset of patients responds to ACT; efforts to identify correlates of response have focused on profiling the tumor or the TIL but rarely in an interactive environment. Interactive profiling can provide unique insights into the clinical performance of TILs since the fate, function, and metabolism of TILs are influenced by autologous tumor-derived factors. Here, we performed a suite of cell-sparing assays dubbed holistic analysis of the bioactivity of interacting T cells and autologous tumor cells (HABITAT). HABITAT profiling of TILs used for human ACT and their autologous tumor cells included function-based single-cell profiling by timelapse imaging microscopy in nanowell grids (TIMING); multi-omics using RNA-sequencing and proteomics; metabolite inference using genome-scale metabolic modeling, and pulse-chase assays based on confocal microscopy to profile the uptake and fate of fatty acids (FA). Phenotypically, the ACT TILs from both responders (Rs) and nonresponders (NRs) were comprised of predominantly effector memory T cells (TEM cells) and did not express a high frequency of programmed death ligand-1 (PD-L1) and showed no differences in TCR diversity. Our results demonstrate that while tumor cells from both Rs and NRs are efficient at uptaking FAs, R TILs are significantly more efficient at utilizing FA through fatty acid oxidation (FAO) than NR TILs under nutrient starvation conditions. While it is likely that lipid and FA uptake is an inherent adaptation of TIL populations to lipid-rich environments, performing FAO sustains the survival of TILs and allows them to sustain antitumor cytolytic activity. We propose that metabolic plasticity enabling FAO is a desirable attribute of human TILs for ACT leading to clinical responses.

2023-05-01 | GSE215037 | GEO

Adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with advanced cervical cancer: a phase 1 trial

Project description:Twenty-seven CC patients with stage III to IV were recruited in this a single-center, phase I study. TILs were isolated from local or metastatic CC lesions and generated under GMP conditions. Thirteen patients accepted TIL-based ACT and intramuscular IL-2 following CCRT or CT treatment. Outcomes were classified as patients with a poor outcome (nonresponders) and patients with a favorable outcome (responders). Single cell RNA sequencing (scRNA-seq) for infused TIL products in responder and non-responder.

2022-07-19 | GSE190075 | GEO

Tumor-reactive clonotype dynamics dictate clinical response to TIL therapy in melanoma [scTCR-seq]

Project description:Although adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is effective in cancer patients, immune correlates of efficacy remain opaque. The profiles, specificity and dynamics of tumor clonotypes expanding in vitro, constituting infusion products and then infiltrating tumors after ACT are poorly understood. We observed that tumor-reactive clonotypes drive clinical response to TIL therapy and provide useful insight to improve patients’ selection or TILs’ expansion methodology.

2023-08-01 | GSE229860 | GEO

Tumor-reactive clonotype dynamics dictate clinical response to TIL therapy in melanoma [scRNA-seq]

2023-08-01 | GSE229858 | GEO

Molecular bases for tumor induced exhaustion in CD8 T cells

Project description:The immune system can recognize and respond to tumors. However there are some conditions in which the genetic instability and heterogeneity of tumor cells leads to the development of variants that can escape the immune system. T cells have infiltrated inside many tumors (Tumor Infiltrating Lymphocytes or TILs), but generally these TILs have lost their functional capacity and are unable to eliminate tumor cells. We developed a model of autochthonous melanoma in mice that recapitulates some aspects of inflammatory melanoma in humans. These include a systemic Th2/Th17-oriented chronic inflammation, recruitment of immunosuppressive myeloid cells and acquisition by TILs of an M-bM-^@M-^\exhaustedM-bM-^@M-^] phenotype characterized by expression of receptors for multiple inhibitory molecules. To address the molecular bases for the M-bM-^@M-^\exhaustedM-bM-^@M-^] TILs phenotype, we performed transcriptomic analyses on sorted CD8 or T cells from the induced melanomas. These transcriptomes were compared to those of naM-CM-/ve CD8 T cells and of CD8 T cells immunized with a virus. 10 samples, 3 replicates for controls (untreated and infected with AdP1A), 4 replicates for TILs CD8 from melanoma

2013-12-31 | E-GEOD-42824 | biostudies-arrayexpress

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