bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2024–12–22
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Advances in Tumor-Infiltrating Lymphocyte (TIL) as a Prognostic Factor and for Treating Invasive Cutaneous Melanoma.
  2. Efficacy of treatment with tumor-infiltrating lymphocytes as adoptive cell therapy: an integrative review.
  3. Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
  4. Tumor infiltrating lymphocytes (TILs) - Pathologia, quo vadis? - A global survey.
  5. Setting "cold" tumors on fire: Cancer therapy with live tumor-targeting bacteria.
  6. Molecular Imaging of Tumor-Infiltrating Lymphocytes in Living Animals Using a Novel mCD3 Fibronectin Scaffold.
  7. Improving Prognostic Value in Invasive Triple Negative Breast Cancer Through a Combined Nomogram Approach.
  8. Identification of a Highly Functional Effector CD8 + T Cell Program after Transplantation in Mice and Humans.
  9. Identification of BIRC5 and HMMR as prognostic biomarkers for immune infiltration in prostate cancer.
  10. Into the Future: Fighting Melanoma with Immunity.
  1. Int J Mol Sci. 2024 Nov 23. pii: 12596. [Epub ahead of print]25(23):
    Advances in Tumor-Infiltrating Lymphocyte (TIL) as a Prognostic Factor and for Treating Invasive Cutaneous Melanoma.
    Gabriel Alves Freiria de Oliveira, Daniel Arcuschin de Oliveira, Melissa Yoshimi Sakamoto Maeda Nisimoto, Rafael Rubinho, Heitor Carvalho Gomes, Luciana Cavalheiro Marti, Renato Santos de Oliveira Filho.
      Invasive cutaneous melanoma is responsible for about 5% of skin tumors yet is liable for nearly 70% of skin cancer-related deaths. Despite notable advancements over the past decade, including immunotherapies and targeted treatments, more than half of invasive melanoma patients ultimately succumb to the disease due to therapeutic resistance. To overcome this obstacle, strategies such as combining immunotherapies with targeted drugs or adding epigenetic therapies have been investigated. Tumor-infiltrating lymphocytes (TILs) therapy has emerged as a promising option for patients whose disease continues to progress despite standard treatments. This article aims to introduce TIL therapy and review recent outcomes in melanoma prognosis in its application for melanoma management.
    Keywords:  cutaneous melanoma; melanoma; metastatic melanoma; tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.3390/ijms252312596
  2. Einstein (Sao Paulo). 2024 ;pii: S1679-45082024000100414. [Epub ahead of print]22 eRW0935
    Efficacy of treatment with tumor-infiltrating lymphocytes as adoptive cell therapy: an integrative review.
    Lucas Marques Soares da Silva, Eleni Solange de Brito Gomes, Julia Hailer Vieira, Murilo Porfírio de Aguiar, Saulo Fernando Moreira da Silva, Marcia Antoniazi Michelin.
       OBJECTIVE: This integrative review article examines the efficacy of adoptive cell therapy using tumor-infiltrating lymphocytes, with a particular focus on the treatment of melanomas and other solid tumors.
    METHODS: The methodology encompasses theme definition, comprehensive database searches, and a critical review of pertinent literature. Of the 1,947 articles initially identified, 15 were meticulously selected based on stringent inclusion and exclusion criteria.
    RESULTS: The findings suggest that tumor-infiltrating lymphocytes-based therapy is particularly effective in treating metastatic melanomas, as noted by its tailored approach and substantial potential. However, the applicability of these findings to other solid tumor types remains limited.
    CONCLUSION: This review indicates that adoptive cell therapy using tumor-infiltrating lymphocytes demonstrates efficacy, especially in the treatment of metastatic melanoma, and shows considerable promise for treating solid tumors.
    DOI:  https://doi.org/10.31744/einstein_journal/2024RW0935
  3. Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244
    Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
    Bing Feng, Rongrong Li, Weilin Li, Li Tang.
      Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
    Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering
    DOI:  https://doi.org/10.1016/j.cels.2024.11.010
  4. Pathol Res Pract. 2024 Dec 13. pii: S0344-0338(24)00686-1. [Epub ahead of print]266 155775
    Tumor infiltrating lymphocytes (TILs) - Pathologia, quo vadis? - A global survey.
    Kristijan Skok, Konstantin Bräutigam.
      Tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment have become increasingly important in cancer research, and immunotherapy has achieved major breakthroughs in improving patient outcomes. Despite the significant role of the pathologist in identifying, subtyping and reporting TILs, the implementation and assessment of TILs in pathology routine remains vague. To assess the actual use of TILs in routine clinical practice, a formal standardized questionnaire was disseminated on two social media platforms ("X" and LinkedIn) and by email in June 2024. Based on the results, we conducted a literature review on TILs via Medline/Pubmed in the two most scored and reported entities, namely malignant melanoma and colorectal cancer (CRC). 77 participants from 24 different countries around the world, mostly pathologists (n = 63, 82.0 %), completed the survey. More than half of the participants do not assess or report TILs in their daily (clinical) practice, a trend consistent across the countries included in the study. A variety of methods are used to report TILs, ranging from Artificial Intelligence (AI)-based scoring algorithms to quantification by eyeballing. Despite recognizing the importance of TIL assessment in clinical routine, many participants find it time-consuming and express a strong preference for AI-based quantification. Our survey reflects the perspective of mostly early career pathologists who recognize the importance of TILs in cancer but face challenges in implementation. The development of AI tools and consensus guidelines could alleviate these barriers. In addition, increasing the visibility and understanding of the role of pathologists within the medical community remains critical.
    Keywords:  Colorectal cancer; Melanoma; Survey; Therapy; Tumor microenvironment (TME); Tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.1016/j.prp.2024.155775
  5. Med. 2024 Dec 11. pii: S2666-6340(24)00443-4. [Epub ahead of print]
    Setting "cold" tumors on fire: Cancer therapy with live tumor-targeting bacteria.
    Simin Manole, Dinh-Huy Nguyen, Jung-Joon Min, Shibin Zhou, Neil Forbes.
      Immunotherapy with checkpoint blockade has shown remarkable efficacy in many patients with a variety of different types of cancer. However, the majority of patients with cancer have yet to benefit from this revolutionary therapy. Studies have shown that checkpoint blockade works best against immune-inflamed tumors characterized by the presence of tumor-infiltrating lymphocytes (TILs). In this review, we summarize studies using live tumor-targeting bacteria to treat cancer and describe various strategies to engineer the tumor-targeting bacteria for maximized immunoregulatory effects. We propose that tumor-localized infections by such engineered bacteria can create an immune microenvironment in favor of a more effective antitumor immunity with or without other therapies, such as immune checkpoint blockade (ICB). Finally, we will briefly outline some exemplary oncology clinical trials involving ICB plus live therapeutic bacteria, with a focus on their ability to modulate antitumor immune responses.
    DOI:  https://doi.org/10.1016/j.medj.2024.11.002
  6. Bioconjug Chem. 2024 Dec 16.
    Molecular Imaging of Tumor-Infiltrating Lymphocytes in Living Animals Using a Novel mCD3 Fibronectin Scaffold.
    Charles Wynter, Arutselvan Natarajan, Clyde John, Kaahini Jain, Ramasamy Paulmurugan.
      The interaction between cancer cells and immune cells in the tumor microenvironment (TME) plays a crucial role in determining tumor growth, metastasis, and response to treatment. Tumor-infiltrating lymphocytes (TILs) in TME could be a predictive marker for treatment response in various therapeutic interventions, including chemotherapy and immunotherapy. Thus, imaging the tumor immune microenvironment is important for selecting the optimal treatment strategies in cancer therapy. The CD3 protein represents a promising target for diagnostic imaging of TILs in vivo to assess the immune state of the TME. Although many anti-CD3 antibodies have been explored for this application, the nonspecific immune activation by these antibodies limits their applications. To overcome this issue, we engineered a novel fibronectin III domain (FN3) protein binder (mCD3-FN3;11.8 kDa) against mouse CD3 antigen protein using a yeast display library to image TILs homing in vivo into the TME. We performed in vitro and in vivo assays to test the mCD3-FN3 binder purity as well as in vivo targetability in mouse models of syngeneic tumors. We used near-infrared 800 dye conjugated with mCD3-FN3 (IR800-mCD3-FN3) for in vivo tracking of TILs via optical imaging. We used three different syngeneic tumors in mice (mCD3+ EL4 tumor in C57BL/6 mice, mCD3- CT26 colon tumor, and mCD3- 4T1 breast tumor in BALB/c mice) for imaging TILs in vivo. C57BL/6 mice bearing EL4 tumors were separated into two groups (blocking [Blk] and nonblocking [Nblk]; n = 3 per group) and used for in vivo imaging. Blocking groups received 200 μg of unlabeled mCD3-FN3 2 h prior to the administration of IR800-mCD3-FN3 binder. Each mouse was administered with 25 μg of the IR800-mCD3-FN3 binder and tracked using an IVIS optical imaging system over time. C57BL/6/EL4 mice were imaged at 4 and 24 h post injection of the IR800-mCD3-FN3 binder, and mouse organs were collected at 24 h after final imaging and used for ex vivo histological imaging. In CT26 and 4T1 tumor models, TILs in TME were imaged 4, 24, and 48 h after binder injection. The NIR imaging of EL4 tumors showed that IR800-mCD3-FN3 can detect both TILs within the tumor and the tumor cells with a high signal-to-background ratio 24 h after initial binder injection with a total radiant efficiency (mean TRE ± SD) of 6.5 × 1010 ± 1.5 × 1010 [photons/s]/[μW/cm2]. The animals received preinjection of unlabeled mCD3-FN3(Blk) prior to IR800-mCD3-FN3 binder administration and showed a significant level of fluorescence signal reduction (mean TRE ± SD: 1.6 × 1010 ± 4.1 × 109) in the tumor when compared to the EL4-Nblk tumors (p = 0.006). The mouse group with CT26 and 4T1 tumors where the probe can only bind to TILs within the tumor showed a specific imaging signal (mean TRE ± SD) of 1.1 × 1011 ± 5.2 × 1010 and 9.5 × 1010 ± 4.6 × 1010, respectively, at 48 h p.i. For these groups, the ex vivo tumor-to-muscle ratios were 20- and 27-fold for CT26 and 4T1 tumors, respectively. These results clearly demonstrate the in vivo binding ability of the mCD3-FN3 binder to mCD3 marker expressed by T cells in the TME. The ex vivo histological analysis of tumors, and the organs of animals with EL4 tumors, and TILs imaging of CT26, and 4T1 tumors (at 48 p.i.) confirmed that the IR800-mCD3-FN3 probe was able to specifically bind to CD3 markers expressed by the T cells. In summary, both in vitro and in vivo data indicated that the engineered mCD3-FN3 binder by this study is a promising ligand for diagnostic imaging of tumors in vivo for the assessment of mCD3 expressing TILs in the TME. This can be used as a prognostic marker in evaluating tumor response to therapeutic intervention as well as a diagnostic marker in imaging tumor response to immune checkpoint blockade cancer therapies.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.4c00501
  7. Clin Breast Cancer. 2024 Nov 22. pii: S1526-8209(24)00319-7. [Epub ahead of print]
    Improving Prognostic Value in Invasive Triple Negative Breast Cancer Through a Combined Nomogram Approach.
    Lian Li, Zhi Liu, Kairong Chen, Yingjia Li.
       OBJECTIVES: To investigate the potential prognostic value of ultrasound (US) features in conjunction with pathological markers and to develop a preliminary working model for predicting poor outcomes in patients with invasive triple-negative breast cancer (TNBC).
    METHODS: From January 2012 to December 2018, we enrolled 209 TNBC patients treated with standard therapy, systematically gathered data on US parameters, stromal tumor-infiltrating lymphocytes (TILs), lymphovascular invasion (LVI) status, and other relevant information, and recorded follow-up data. A nomogram combining AJCC staging with US score, stromal TILs, and LVI was constructed and validated to predict poor outcomes, defined as recurrence or death, in patients with invasive TNBC.
    RESULTS: The US score of 4 was best related to poor outcomes in patients with TNBC (HR 3.87, P = .015). In the training set, the nomogram had a considerably greater prognostic value [area under the curve (AUC), 0.74 vs. 0.64, P = .045] than AJCC staging alone, and it was comparable to that of the validation set (AUC, 0.71 vs. 0.63, P = .804). An acceptable consistency between the nomogram-predicted and actual survival probabilities was found both in the training and validation sets, with Brier scores of 0.15 and 0.13, respectively.
    CONCLUSIONS: The incorporation of AJCC stage with US score, stromal TILs, and LVI improved the model performance for predicting poor outcomes in patients with invasive TNBC compared to routine AJCC staging alone.
    Keywords:  Disease-free survival; Lymphovascular invasion; Prognosis; Stromal tumor-infiltrating lymphocytes; Ultrasound
    DOI:  https://doi.org/10.1016/j.clbc.2024.11.013
  8. bioRxiv. 2024 Dec 02. pii: 2024.11.26.625263. [Epub ahead of print]
    Identification of a Highly Functional Effector CD8 + T Cell Program after Transplantation in Mice and Humans.
    Gregory S Cohen, Joel S Freibaum, Riley P Leathem, Ryo Hatano, Chikao Morimoto, Scott M Krummey.
      Acute T cell mediated rejection of allografts remains a significant risk factor for early graft loss. Our prior work defined a population of graft-specific CD8 + T cells positive for the activated receptor CD43 (expressing the 1B11 epitope) that form during acute rejection, leading us to further understand the in vivo fate and clinical relevance of this population. We found that during acute rejection, the CD43 + ICOS + phenotype was sensitive for proliferative graft-specific CD8 + T cells. We evaluated whether CD43 1B11 signaling could impact graft survival, and found that CD43 1B11 mAb treatment could overcome costimulation-blockade induced tolerance in the majority of mice. Using an adoptive transfer approach, we investigated the fate of CD43 1B11 + and CD43 1B11 - CD8 + T cell populations, and found that CD43 1B11 + CD8 + T cells were more persistent three weeks after transplantation. A portion of CD43 1B11 - CD8 + T cells converted to CD43 1B11 + , while CD43 1B11 + CD8 + T cells retained CD43 1B11 + status. In healthy human donors, we found that the CD43 1D4 clone, which identifies the large CD43 isoform, defines a population of antigen-experienced CD8 + T cells independent of the canonical CD8 + T cell populations. CD43 1D4 + CD8 + T cells were efficient cytokine-producers after stimulation. In scRNA-seq analysis of graft-infiltrating cells from renal transplant patients experiencing acute rejection, a population of SPN + GCNT1 + CD8 + T cells had an effector phenotype that includes high expression of IFNG, ICOS, and perforins/granzymes. Together, these data provide evidence that the CD43 1B11 expression defines a proliferative and persistent population of CD8 + T cells in mice, and that an analogous population of antigen-experienced CD8 + T cells that participate in allograft rejection.
    DOI:  https://doi.org/10.1101/2024.11.26.625263
  9. Transl Androl Urol. 2024 Nov 30. 13(11): 2482-2497
    Identification of BIRC5 and HMMR as prognostic biomarkers for immune infiltration in prostate cancer.
    Huarui Tang, Fanyang Zhou, Wentao Hu, Chen Zhang, Jianping Tao, Fawang Xing, Zhenxing Zhang, Yukui Gao.
       Background: Understanding the molecular mechanisms and identifying prognostic markers across various subtypes and stages of prostate cancer (PCa) are crucial for improving therapeutic strategies against the disease. This study focuses on discovering novel immune-related biomarkers that could aid in the evaluation and prognosis of PCa at different stages and serve as promising therapeutic targets.
    Methods: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to identify differentially expressed genes (DEGs) linked to PCa progression. The relationship between immune cell infiltration in the tumor microenvironment (TME) and the expression levels of baculoviral inhibitor of apoptosis protein repeat containing 5 (BIRC5) and hyaluronan-mediated motility receptor (HMMR) were examined using xCELL and quanTIseq algorithms.
    Results: The analysis identified ten key hub genes, with survival analysis indicating that higher expressions of BIRC5 and HMMR were associated with poor outcomes and may contribute to tumor progression. Notably, the expressions of BIRC5 and HMMR showed a significant correlation with tumor-infiltrating lymphocytes (TILs) in various PCa subgroups. Immunohistochemistry (IHC) evaluations further corroborated the bioinformatics findings.
    Conclusions: This study confirms BIRC5 and HMMR as potential biomarkers for predicting the prognosis of PCa, providing important evidence for the development of future therapeutic strategies. Through further research, these biomarkers may be utilized in clinical practice to improve patient management and treatment outcomes.
    Keywords:  Prostate cancer (PCa); hub genes; immune infiltration; prognostic biomarkers; subgroup of prostate cancer (subgroup of PCa)
    DOI:  https://doi.org/10.21037/tau-24-359
  10. Cancers (Basel). 2024 Nov 29. pii: 4002. [Epub ahead of print]16(23):
    Into the Future: Fighting Melanoma with Immunity.
    Derek A Corica, Scott D Bell, Peyton J Miller, Daniel T Kasperbauer, Nicholas J Lawler, Mark R Wakefield, Yujiang Fang.
      Immunotherapy offers a novel and promising option in the treatment of late-stage melanoma. By utilizing the immune system to assist in tumor destruction, patients have additional options after tumor progression. Immune checkpoint inhibitors reduce the ability for tumors to evade the immune system by inhibiting key surface proteins used to inactivate T-cells. Without these surface proteins, T-cells can induce cytotoxic responses against tumors. Tumor infiltrating lymphocyte therapy is a form of adoptive cell therapy that takes advantage of a small subset of T-cells that recognize and infiltrate tumors. Isolation and rapid expansion of these colonies assist the immune system in mounting a charged response that can induce remission. Tumor vaccines deliver a high dose of unique antigens expressed by tumor cells to the entire body. The introduction of large quantities of tumor antigens upregulates antigen presenting cells and leads to effective activation of the immune system against tumors. Cytokine therapy introduces high amounts of chemical messengers that are endogenous to the immune system and support T-cell expansion. While other methods of immunotherapy exist, immune checkpoint inhibitors, tumor infiltrating lymphocytes, tumor vaccines, and cytokine therapy are commonly used to treat melanoma. Like many other cancer treatments, immunotherapy is not without adverse effects, as toxicities represent a major obstacle. However, immunotherapy has been efficacious in the treatment of melanoma.
    Keywords:  melanoma; melanoma immunotherapy; melanoma treatment
    DOI:  https://doi.org/10.3390/cancers16234002
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