bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2024–11–24
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: A Review.
  2. Collagen-disruptive cell therapy: adoptive transfer of membrane-anchored, tumor cell surface vimentin-targeted interleukin 12-armed TILs suppress collagen expression to boost deep T-cell infiltration via dual signaling activation and significant CCKAR reduction.
  3. Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development.
  4. Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.
  5. The prognostic value of tumor-infiltrating lymphocytes in vulvovaginal melanoma.
  6. Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC.
  7. Prognostic significance of CD8 and TCF1 double positive T cell subset in microsatellite unstable gastric cancer.
  8. Ectopic expression of NKG7 enhances CAR-T function and improves the therapeutic efficacy in liquid and solid tumors.
  1. JCO Precis Oncol. 2024 Oct;8 e2400183
    CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: A Review.
    Kevin J Contrera, Matthew E Spector, Liron Pantanowitz, Ibrahim M Abukhiran, Lazar Vujanovic, Theresa L Whiteside, Yvonne M Mowery, Dan P Zandberg, Shaum S Sriharan, Seungwon Kim, Christopher Wilke, Heath D Skinner, Jose P Zevallos, Robert L Ferris.
      CD8+ tumor-infiltrating lymphocytes (TILs) are increasingly used in oncology as a prognostic and predictive tool to guide patient management. This review summarizes current literature on CD8+ TILs in head and neck squamous cell carcinoma (SCC). Published meta-analyses and clinical trials evaluating CD8+ TILs were analyzed. Consistent positive associations between elevated CD8+ TILs and overall survival have been observed across head and neck sites. CD8+ TILs have been found to predict response to treatment, most commonly immunotherapy, but also chemoradiation. Numerous trials have shown that increased CD8+ TIL frequencies in pretreatment biopsies could identify patients likely to respond to neoadjuvant therapies. CD8+ TIL infiltration has also been elevated in responders both during and after treatment. However, wider adoption of CD8+ TIL quantification as a biomarker has been limited by the need for clinical validation and universal measurement guidelines for head and neck SCC, as there are for other malignancies. Measurement variability includes which tumor compartment is sampled, how TILs are quantified, and which cutoffs are clinically relevant. For several head and neck SCC, measurement of CD8+ TILs in the central or intratumoral compartment, followed by the stromal compartment, has been most consistently associated with survival. Future studies are needed to evaluate subpopulations of CD8+ TILs and biomarker-based treatment selection.
    DOI:  https://doi.org/10.1200/PO.24.00183
  2. Res Sq. 2024 Oct 29. pii: rs.3.rs-5104493. [Epub ahead of print]
    Collagen-disruptive cell therapy: adoptive transfer of membrane-anchored, tumor cell surface vimentin-targeted interleukin 12-armed TILs suppress collagen expression to boost deep T-cell infiltration via dual signaling activation and significant CCKAR reduction.
    Shulin Li.
      Tumor-targeted T-cell therapies of various types have been booming, but T-cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell surface vimentin (CSV)-targeted and membrane-anchored IL12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, thereby increasing T-cell infiltration. However, attIL12-T cells cannot reduce collagen expression by tumors that highly express CCKAR. In this study, we discovered that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and HLA-TCR on attIL12-TILs; when either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells synergized IFNγ production, which in combination with CCKAR downregulation reduced collagen expression through suppression of both TGFβ-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T-cell infiltration and improved tumor growth inhibition in PDX sarcomas. This study thus uncovers the first tumor collagen-disrupting T-cell therapy we know of. This is significant because collagen is enriched in most high-grade CCKAR+ human sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T-cell infiltration in high-grade, collagen-rich tumors.
    DOI:  https://doi.org/10.21203/rs.3.rs-5104493/v1
  3. Oncol Res. 2024 ;32(12): 1837-1850
    Exploring the therapeutic potential of precision T-Cell Receptors (TCRs) in targeting KRAS G12D cancer through in vitro development.
    Weitao Zheng, Dong Jiang, Songen Chen, Meiling Wu, Baoqi Yan, Jiahui Zhai, Yunqiang Shi, Bin Xie, Xingwang Xie, Kanghong Hu, Wenxue Ma.
       Objectives: The Kirsten rat sarcoma virus (KRAS) G12D oncogenic mutation poses a significant challenge in treating solid tumors due to the lack of specific and effective therapeutic interventions. This study aims to explore innovative approaches in T cell receptor (TCR) engineering and characterization to target the KRAS G12D7-16 mutation, providing potential strategies for overcoming this therapeutic challenge.
    Methods: In this innovative study, we engineered and characterized two T cell receptors (TCRs), KDA11-01 and KDA11-02 with high affinity for the KRAS G12D7-16 mutation. These TCRs were isolated from tumor-infiltrating lymphocytes (TILs) derived from tumor tissues of patients with the KRAS G12D mutation. We assessed their specificity and anti-tumor activity in vitro using various cancer cell lines.
    Results: KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope, significantly inducing IFN-γ release and eliminating tumor cells without cross-reactivity or alloreactivity.
    Conclusions: The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation, showing potential for significant advancements in cancer immunotherapy.
    Keywords:  Alloreactivity; G12D; Kirsten rat sarcoma virus (KRAS); T cell receptor (TCR); TCR therapy; Tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.32604/or.2024.056565
  4. bioRxiv. 2024 Nov 02. pii: 2024.10.29.620864. [Epub ahead of print]
    Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.
    Chin-Chih Liu, Dennis Grencewicz, Karthik Chakravarthy, Lin Li, Ruth Liepold, Matthew Wolf, Naseer Sangwan, Alice Tzeng, Rebecca Hoyd, Sachin R Jhawar, Stephen R Grobmyer, Zahraa Al-Hilli, Andrew P Sciallis, Daniel Spakowicz, Ying Ni, Charis Eng.
       Background: Breast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8+ tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8+ TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome.
    Methods: We investigated the interplay among CD8+ TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8+ TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC).
    Results: In tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8+ TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus-positive versus Staphylococcus-negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8+ TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus, the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8+ TILs.
    Conclusions: We identified specific metabolites and microbial taxa associated with CD8+ TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.
    Keywords:  Microbiome; S. aureus; Staphylococcus; T cells; anti-tumor immunity; breast cancer; metabolism; metabolome; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1101/2024.10.29.620864
  5. Int J Gynecol Cancer. 2024 Nov 19. pii: ijgc-2024-005359. [Epub ahead of print]
    The prognostic value of tumor-infiltrating lymphocytes in vulvovaginal melanoma.
    Margaux Vanbockstael, Guillaume Bataillon, Mathilde Morisseau, Gwenael Ferron, Justine Attal, Thomas Meresse, Emilie Tournier, Yann Tanguy Le Gac, Cécile Pages, Alejandra Martinez.
       OBJECTIVE: To assess the relation between immune microenvironment, survival, and clinicopathological characteristics.
    METHODS: This study was a retrospective, single-center, observational study. Patients with a vulvovaginal melanoma and available archived material were included. All cases underwent pathology review, tumor-infiltrating lymphocyte quantification, and next-generation sequencing analysis, when feasible. Clinical data included demographic, treatment, and prognostic data.
    RESULTS: Forty-two patients were selected during the study period, but 13 were finally excluded owing to unavailable formalin-fixed, paraffin-embedded material or unknown follow-up data. Twelve of 19 cases (63.2%) had at least one genetic mutation, 3/18 (16.7%) had BRAF, 3/18 (16.7%) had c-KIT mutation, and 4/17 (23.5%) had NRAS mutations. High stromal tumor-infiltrating lymphocytes were identified in 13/28 patients (46.4%), and brisk tumor-infiltrating lymphocytes in 17/28 patients (60.7%). A density of stromal tumor-infiltrating lymphocytes >40% and brisk distribution were the single clinicopathologic factor associated with increased disease-free survival.
    CONCLUSION: The study showed that brisk tumor-infiltrating lymphocytes and stromal tumor-infiltrating lymphocytes were a marker for disease progression, and for response to immunotherapy strategies. To validate these findings on a larger scale, further research is warranted through a multicenter study with a larger cohort and additional genetic and translational analysis.
    Keywords:  Melanoma; Pathology; Vulvar Neoplasms; Vulvar and Vaginal Cancer
    DOI:  https://doi.org/10.1136/ijgc-2024-005359
  6. Cancer Gene Ther. 2024 Nov 20.
    Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC.
    Kai Ye, Yongfeng Yan, Rui Su, Qinghai Dai, Kunyan Qiao, Yu Cao, Jian Xu, Lihua Yan, Zhixiao Huo, Wei Liu, Yue Hu, Yu Zhu, Liang Xu, Yuqiang Mi.
      Previous studies have found that oncolytic virus (OVs) can improve the efficacy of TIL adoptive therapy in oral cancer, colon cancer, and pancreatic cancer. However, the curative effect in hepatocellular carcinoma (HCC) is still unclear. Therefore, this study aims to explore the therapeutic effect and mechanism of OVs encoding 4-1BBL and IL15 (OV-4-1BBL/IL15) combined with TIL adoptive therapy on HCC. In this study, the role and immunological mechanism of armed OVs combined with TILs were evaluated by flow cytometry and ELISA in patient-derived xenograft and syngeneic mouse tumor models. Co-culturing with TILs can up-regulate the expression of antigen-presenting cell (APC) markers on the surface of OV-infected primary HCC cells, and promote the specific activation ability and tumor-killing ability of TILs. OV-4-1BBL/IL15 combined with TIL adoptive therapy could induce tumor volume reduction and anti-tumor immune memory in patient-derived xenograft and syngeneic mouse tumor models. Furthermore, OV combined with TIL adoptive therapy can endow tumor cells with aAPC characteristics, activate T cells at the same time, and reprogram tumor macrophages into anti-tumor phenotype. OV-4-1BBL/IL15 can stimulate the anti-tumor potential of TIL therapy in HCC, and possess broad clinical application prospects.
    DOI:  https://doi.org/10.1038/s41417-024-00853-w
  7. Sci Rep. 2024 Nov 21. 14(1): 28810
    Prognostic significance of CD8 and TCF1 double positive T cell subset in microsatellite unstable gastric cancer.
    Juhyeong Park, Soo Kyung Nam, Yoonjin Kwak, Hyeon Jeong Oh, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Han-Kwang Yang, Hye Seung Lee.
      Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R2 = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC.
    Keywords:  Alpha E integrins; Microsatellite instability; Stomach neoplasms; T cell transcription factor 1; Tumor-Infiltrating Lymphocytes
    DOI:  https://doi.org/10.1038/s41598-024-80450-x
  8. Pharmacol Res. 2024 Nov 17. pii: S1043-6618(24)00451-1. [Epub ahead of print]210 107506
    Ectopic expression of NKG7 enhances CAR-T function and improves the therapeutic efficacy in liquid and solid tumors.
    Yuxin Chen, Meng Wang, Shuxin Huang, Lulu Han, Ying Cai, Xiaodi Xu, Shuwen Sun, Zhaokai Chen, Junze Chen, Jiatian Yu, Hongwei Du, Huizhong Li, Junnian Zheng, Bo Ma, Gang Wang.
      Lack of biopsies after treatment, especially in solid tumors, restricts the understanding of chimeric antigen receptor (CAR)-T cells -related characteristic in vivo, thus hindering the development of strategies to improve CAR-T cells efficacy. Here, we applied nineteen individual single-cell RNA sequencing (scRNA-seq) data from clinical samples of digestive cancers to explore the characteristics of tumor-infiltrating T cells (TILs) to identify effective targets which might be benefit for enhancing the function of CAR-T cells. The data showed that natural killer cell granule protein 7 (NKG7) was overexpressed in TILs and positively associated with anti-PD1 or anti-CTLA4 therapy in digestive cancers. Subsequently, we found that ectopic expression of NKG7 significantly improved the cytotoxicity of B7H3-targeting CAR-T cells to B7H3-positive digestive cancer cells (MKN45, Huh7, HuCCT-1, SW620 and PANC-1 cells), as well as promoted the TNF-α and IL-2 expression. Furthermore, in a CD19-targeting CAR-T model, the therapeutic efficacy was also found increased after NKG7 overexpression. Mechanically, NKG7 preserved surface CAR expression and promoted CAR-T cell proliferation after exposing to relative tumor antigen. These results indicated that it may be feasible to explore single-cell sequencing data of clinical tumor samples to find strategies to improve CAR-T function, and that ectopic expression of NKG7 is an effective strategy to improve the therapeutic efficacy of CAR-T cells against tumors.
    Keywords:  CAR-T; Hematologic malignancies; IL-2 signaling pathway; Immunotherapy; Solid tumors
    DOI:  https://doi.org/10.1016/j.phrs.2024.107506
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒24 at 1:57.