bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2024–12–15
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Effect of hypoxia-induced mIL15 expression on expansion and memory progenitor stem-like TILs in vitro.
  2. Tumor-infiltrating lymphocytes vary in different canine soft tissue sarcoma histological types.
  3. The Prognostic Significance of Tumor Budding and Tumor-Infiltrating Lymphocytes in Patients Diagnosed With Malignant Melanoma.
  4. Lymphocyte infiltration in breast cancer: A promising prognostic indicator.
  5. Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer.
  6. Tumor-Infiltrating Lymphocytes as Mediators of the Obesity and Papillary Thyroid Carcinoma Lymph Node Metastasis Association: An Observational Retrospective Cohort Study.
  7. Complete remission after pembrolizumab monotherapy in a non-small cell lung cancer patient with PD-L1 negative, high tumor mutational burden, and positive tumor-infiltrating lymphocytes: A case report.
  8. Characterization of tumor microenvironment and cell interaction patterns in testicular and diffuse large B-cell lymphomas.
  9. LRP1B Suppresses Immunotherapy Efficacy in Lung Adenocarcinoma by Preventing Ferroptosis.
  10. Ex vivo expansion and hydrogel-mediated in vivo delivery of tissue-resident memory T cells for immunotherapy.
  11. The function of CD8 + T cells in the absence of MHC-I in target cells: what to learn from the deficiency of MHC-I expression in humans.
  12. Tumor-Infiltrating Immune Cells in Colorectal Cancer.
  13. Breaking the mold: Unconventional T cells in cancer therapy.
  14. Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
  15. T cell dynamics with neoadjuvant immunotherapy in head and neck cancer.
  16. T-switch-ing TCR specificity.
  17. Myeloid effector cells in cancer.
  18. Decoding NY-ESO-1 TCR T cells: transcriptomic insights reveal dual mechanisms of tumor targeting in a melanoma murine xenograft model.
  19. Preclinical Evaluation and Pilot Clinical Study of CD137 PET Radiotracer for Noninvasive Monitoring Early Responses of Immunotherapy.
  1. Front Immunol. 2024 ;15 1450245
    Effect of hypoxia-induced mIL15 expression on expansion and memory progenitor stem-like TILs in vitro.
    Zhen Sun, Aotian Xu, Zhaojun Wu, Xiaohao Lan, Ganchen Gao, Bin Guo, Zhongjie Yu, Lin Shao, Hao Wu, Min Lv, Yongjie Wang, Yi Zhao, Bin Wang.
       Introduction: The adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) has proven clinically beneficial in patients with non-small cell lung cancer refractory to checkpoint blockade immunotherapy, which has prompted interest in TIL-adoptive cell transfer. The transgenic expression of IL15 can promote the expansion, survival, and function of T cells ex vivo and in vivo and enhance their anti-tumor activity. The effect of expressing mIL15 regulated by hypoxia in the tumor microenvironment on the expansion, survival, and stem-like properties of TILs has not been explored.
    Methods: Using TILs expanded from the tumor tissues of lung cancer patients, TILs with or without mIL15 expression (TIL-mIL15 or UN-TIL) were generated by lentiviral transduction. To reflect the advantages of mTIL15, the cells were divided into groups with IL2 (TIL-mIL15+IL2) or without IL2 (TIL-mIL15-IL2).
    Results: Compared to UN-TIL cells, mIL15 expression had a similar capacity for promoting TIL proliferation and maintaining cell viability. Our experimental findings indicate that, compared to UN-TIL and TIL-mIL15+IL2 cells, the expression of mIL15 in TIL-mIL15-IL2 cells promoted the formation of stem-like TILs (CD8+CD39-CD69-) and led to significant decreases in the proportion and absolute number of terminally differentiated TILs (CD8+CD39+CD69+). RNA-Seq data revealed that in TIL-mIL15-IL2 cells, the expression of genes related to T cell differentiation and effector function, including PRDM1, ID2, EOMES, IFNG, GZMB, and TNF, were significantly decreased, whereas the expression of the memory stem-like T cell marker TCF7 was significantly increased. Furthermore, compared to UN-TIL and TIL-mIL15+IL2 cells, TIL-mIL15-IL2 cells showed significantly lower expression levels of inhibitory receptors LAG3, TIGIT, and TIM3, which was consistent with the RNA-Seq results.
    Discussion: This study demonstrates the superior persistence of TIL-mIL15-IL2 cells, which may serve as a novel treatment strategy for lung cancer patients.
    Keywords:  adoptive cell transfer; expansion; hypoxia regulation; immunotherapy; lung cancer; membrane-bound interleukin 15; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2024.1450245
  2. Vet Pathol. 2024 Dec 09. 3009858241300556
    Tumor-infiltrating lymphocytes vary in different canine soft tissue sarcoma histological types.
    Giancarlo Avallone, Elena Brigandì, Chiara Tugnoli, Antonella Rigillo, Barbara Bacci, Paola Roccabianca.
      Soft tissue sarcomas (STSs) are conventionally viewed as poorly immunogenic tumors; however, some human STSs have recently been reported to elicit an immune response, thus representing potential candidates for immunotherapy. Data regarding immune cell infiltrates in canine STSs are limited and reported without tumor-type stratification. The aim of this study was to retrospectively assess tumor-infiltrating lymphocytes (TILs) in canine STSs of 5 different histotypes. Eighty-seven canine STSs were collected: 22 perivascular wall tumors (PWTs), 19 liposarcomas, 17 fibrosarcomas, 16 myxosarcomas, and 13 leiomyosarcomas. The tumors were graded and immunolabeled for CD3, CD20, and FoxP3, and slides were scanned. T-cell, B-cell, Treg, and total TIL densities were quantified with QuPath software and expressed as cells/mm2. The B/T-cells ratio and Treg/T-cell proportions were calculated. Total TIL densities were higher in PWTs and myxosarcomas (median = 225 and 303, respectively). PWTs had higher T-cell density but lower Treg proportion (median = 152 and 7.6% respectively). Myxosarcomas had higher Treg densities and B/T-cell ratios (median = 24.4 and 1.57, respectively). No association with grade was found among STSs as a group. In myxosarcomas, higher grade was significantly associated with higher total TILs, and CD20+ and FoxP3+ cell densities (p < .05). The results suggest that PWTs and myxosarcomas may represent the most immunogenic STS types. Myxosarcomas elicit a B-cell and Treg-rich immune response; PWTs stimulate a T-cell-rich and Treg-poor reaction. The immune system response may contribute to the more aggressive behavior of myxosarcomas and the more indolent course of PWTs.
    Keywords:  canine; image analysis; soft tissue sarcoma; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1177/03009858241300556
  3. Am J Dermatopathol. 2024 Dec 10.
    The Prognostic Significance of Tumor Budding and Tumor-Infiltrating Lymphocytes in Patients Diagnosed With Malignant Melanoma.
    Ayşen Yavuz, Kübra Şimşek, Cumhur İbrahim Başsorgun, Gülsüm Özlem Elpek, Betül Ünal.
       ABSTRACT: The tumor microenvironment plays a critical role in malignant melanoma, influencing progression and patient outcomes, particularly through tumor budding (TB) and tumor-infiltrating lymphocytes (TILs). Despite the importance of TB, its detailed impact still needs to be explored, especially its interaction with TILs. This study evaluates the prognostic significance of TB and TILs in malignant melanoma, assessing their potential as indicators for disease progression and survival. Conducted at Akdeniz University, the research included 92 patients diagnosed between 2014 and 2021. TB was evaluated according to the International Tumor Budding Consensus Conference guidelines, and TILs were assessed by the International Immuno-Oncology Biomarker Working Group standards. The analysis revealed significant correlations between TB and the level of anatomic invasion, Breslow thickness, satellite nodules, lymph node metastasis, distant metastasis, and stage (P < 0.05). A notable inverse relationship between TB and intratumoral TILs suggested their different roles in tumor progression. Tumor subtype, level of anatomic invasion, satellite nodules, lymphovascular invasion, lymph node metastasis, distant metastasis, stage, TILs, and TB were significant risk factors associated with poor prognosis (P < 0.005). Multivariate Cox regression identified histologic subtype and TB >10 as independent prognostic factors, underscoring the need for further research to integrate TB and TILs into clinical practice for better patient management and treatment planning.
    DOI:  https://doi.org/10.1097/DAD.0000000000002902
  4. Medicine (Baltimore). 2024 Dec 06. 103(49): e40845
    Lymphocyte infiltration in breast cancer: A promising prognostic indicator.
    Emmanuel Ifeanyi Obeagu, Getrude Uzoma Obeagu.
      Breast cancer is a leading cause of cancer-related mortality among women worldwide, necessitating the identification of reliable prognostic markers to guide treatment and improve patient outcomes. Recent research has highlighted the prognostic significance of tumor-infiltrating lymphocytes (TILs) in breast cancer, with high levels of TILs being associated with improved survival rates and better responses to therapy. This review delves into the mechanisms driving lymphocyte infiltration, its clinical implications, and the potential for TILs to serve as predictive biomarkers in breast cancer management. The presence of TILs within the tumor microenvironment reflects a dynamic interplay between tumor cells and the host immune system. Chemokine signaling, antigen presentation, and immune checkpoint interactions are key mechanisms that facilitate the recruitment and activity of lymphocytes at the tumor site. Clinically, the density of TILs varies across breast cancer subtypes, with the most significant prognostic value observed in triple-negative and HER2-positive breast cancers. High TIL levels correlate with improved overall survival and disease-free survival, underscoring their potential as a valuable prognostic indicator. Therapeutically, the role of TILs has opened new avenues in breast cancer treatment, particularly in the realm of immunotherapy. Immune checkpoint inhibitors, adoptive cell therapy, and combination therapies leveraging TILs are being explored to enhance antitumor responses. As research progresses, the integration of TIL assessment into routine clinical practice could revolutionize personalized treatment strategies, ultimately improving prognostic accuracy and patient outcomes in breast cancer care.
    DOI:  https://doi.org/10.1097/MD.0000000000040845
  5. Breast Cancer Res. 2024 Dec 06. 26(1): 180
    Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer.
    Eunkyung Han, Hye Yeon Choi, Hyun Jung Kwon, Yul Ri Chung, Hee-Chul Shin, Eun-Kyu Kim, Koung Jin Suh, Se Hyun Kim, Jee Hyun Kim, So Yeon Park.
       BACKGROUND: The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response in triple-negative breast cancers (TNBCs). This study was aimed to characterize the composition of TILs and investigate their clinicopathological and prognostic significance with a special focus on the spatial distribution of TILs in TNBCs.
    METHODS: We analyzed TNBC samples through PanCancer Immune Profiling using NanoString nCounter assays to identify immune-related genes that are expressed differentially in relation to TIL levels and evaluated protein expression of selected markers through immunohistochemical staining on tissue microarrays. For a comprehensive assessment of the expression of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell markers, a CTL-NK score was devised based on CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL levels.
    RESULTS: Gene expression analysis revealed significant upregulation of CTL and NK cell-associated genes including GNLY, KLRC2, and GZMB in TIL-high TNBCs. Immunohistochemical validation confirmed that TNBCs with higher TILs had a greater amount of CD56+, CD57+, GNLY+, and GZMB+ TILs not only in absolute number but also in proportion relative to CD4+ or CD8+ TILs. High TIL and its subset (CD4+, CD8+, CD56+, CD57+, GNLY+, and GZMB+ TIL) infiltration correlated with favorable clinicopathological features of tumor. In survival analysis, high CTL-NK score was found to be an independent prognostic factor for better disease-free survival (DFS) of the patients. Furthermore, uniformly high TIL infiltration was linked to better DFS, whereas cases with heterogeneous TIL infiltration showed no difference in survival compared to those with uniformly low TIL infiltration.
    CONCLUSION: Our study showed that CTL and NK cell-associated gene expression and protein levels differ significantly according to TIL levels and that CTL-NK score and distribution of TILs within tumors have a prognostic value. These findings emphasize the importance of CTLs and NK cells as well as the spatial uniformity of TIL infiltration in clinical outcome of TNBC patients, providing valuable insights for refining prognostic assessments and guiding immunotherapeutic strategies.
    Keywords:  Cytotoxic T lymphocyte; NK cell; Spatial distribution; Triple-negative breast cancer; Tumor infiltrating lymphocyte
    DOI:  https://doi.org/10.1186/s13058-024-01932-4
  6. Ann Surg Oncol. 2024 Dec 10.
    Tumor-Infiltrating Lymphocytes as Mediators of the Obesity and Papillary Thyroid Carcinoma Lymph Node Metastasis Association: An Observational Retrospective Cohort Study.
    Jiao Zhang, Changlin Li, Gianlorenzo Dionigi, Hui Sun.
       BACKGROUND: Obesity increases the risk of papillary thyroid carcinoma (PTC) and lymph node metastasis (LNM), possibly via modulation of the tumor immunological microenvironment.
    MATERIALS AND METHODS: The STROCSS guideline was followed to conduct a retrospective cohort study. Binary logistic regression analysis with odds ratios (OR) was performed to assess the association between tumor-infiltrating lymphocytes (TILs), obesity, and LNM. Using The Cancer Genome Atlas (TCGA) data, we examined the relationship between immune cell subsets and obesity-regulating molecules in thyroid cancer tissues. The Cox regression risk model was used to analyze the prognosis of thyroid cancer.
    RESULTS: After adjusting for confounding factors, our findings revealed that overweight and obesity were associated with a decrease in TIL infiltration (OR 0.876, p = 0.005 and OR 0.795, p = 0.001, respectively). Furthermore, these conditions were observed to be correlated with increased likelihood of LNM (OR 1.134, p = 0.005 and OR 1.307, p < 0.001, respectively). On the contrary, TIL infiltration was inversely associated with LNM (OR 0.868, p < 0.001). When controlling for TIL infiltration as the sole variable, the combination of obesity and TIL infiltration did not independently predict LNM (adjusted OR 1.442, p = 0.113). However, obesity alone was found to elevate the likelihood of LNM (adjusted OR 1.539, p = 0.02). Additionally, adiponectin (a crucial adipokine) was reduced in obesity and demonstrated a negative correlation with the abundance of infiltrated dendritic cells and regulatory T cells, as evidenced by TCGA data analysis. Furthermore, ADIPOR2 expression negatively correlated with LNM and positively associated with unfavorable prognosis in PTC, with a hazard ratio of 0.480 (p = 0.007).
    CONCLUSIONS: TIL infiltration may affect obesity-associated PTC LNM. Obesity may affect LNM and result in poor prognosis through ADIPOR2 regulation of antitumor immune cells.
    Keywords:  ADIPOR2; Lymph node metastasis; Obesity; Papillary thyroid cancer; Tumor immunity; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1245/s10434-024-16647-1
  7. Medicine (Baltimore). 2024 Dec 06. 103(49): e40369
    Complete remission after pembrolizumab monotherapy in a non-small cell lung cancer patient with PD-L1 negative, high tumor mutational burden, and positive tumor-infiltrating lymphocytes: A case report.
    Suoni Li, Jiequn Ma, Jie Bai, Zheng Zhao.
       RATIONALE: Immune checkpoint inhibitors have been used to treat cancer patients. Non-small cell lung cancer (NSCLC) patients with a high expression level of programmed cell death ligand-1 (PD-L1) could benefit from immune checkpoint inhibitor monotherapy. However, treating NSCLC patients with PD-L1 negative is still a clinical challenge. The utilization of new-type tumor markers as predictive indicators of therapeutic efficacy, with the aim of guiding clinical medication strategies, has emerged as a paramount focus of clinical investigation and interest.
    PATIENT CONCERNS AND DIAGNOSES: We reported a 72-year-old male with cough diagnosed as poorly differentiated metastatic lung adenocarcinoma (cT3N2M1, stage IV). He tested negative for driver gene mutations, and PD-L1 negative (＜1%), but a high tumor mutational burden (30.9 and 39.1 mutations/Mb in the lung tissue and blood, respectively), and positive tumor-infiltrating lymphocytes.
    INTERVENTIONS: The patient received pembrolizumab monotherapy.
    OUTCOMES: After 8 treatment cycles over 5 months, repeat examinations showed significantly reduced lung mass and circulating tumor DNA abundance. The patient reached clinical complete remission and had long-term survival with no significant adverse events.
    LESSONS: A comprehensive evaluation of multiple tumor biomarkers should be considered in NSCLC patients. Pembrolizumab monotherapy could benefit NSCLC patients with negative driver genes, PD-L1 negative, a high tumor mutational burden, and positive tumor-infiltrating lymphocytes.
    DOI:  https://doi.org/10.1097/MD.0000000000040369
  8. Haematologica. 2024 Dec 12.
    Characterization of tumor microenvironment and cell interaction patterns in testicular and diffuse large B-cell lymphomas.
    Matias Autio, Oscar Brück, Marjukka Pollari, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Judit Mészaros Jørgensen, Harald Holte, Teijo Pellinen, Suvi-Katri Leivonen, Sirpa Leppä.
      The tumor microenvironments (TME) of diffuse large B-cell lymphoma (DLBCL) subgroups have remained poorly characterized. Here, we dissected the composition and spatial organization of the TME in germinal center B-cell (GCB), activated B-cell (ABC), and testicular DLBCLs (T-DLBCL) using gene expression profiling and multiplex immunohistochemistry. We found that high proportions of M2-like tumor-associated macrophages (TAMs) and cytotoxic tumor-infiltrating T cells (TILs) were characteristic of ABC DLBCL TME. Furthermore, high CD8+ TIL content translated to favorable outcomes. In contrast, GCB DLBCL TME was enriched in CD4+ TILs, regulatory TILs, and a higher M1-like/M2-like TAM ratio, and high proportions of TAMs and Granzyme B+ cells associated with worse survival. TILs and TAMs interacted more frequently with M2-like TAMs and cytotoxic TILs in the ABC DLBCLs contrary to GCB subtype, where the interactions were more abundant with other TILs and CD4+ TILs. In T-DLBCL, TME resembled that of ABC DLBCL with a higher proportion of M2-like TAMs and cytotoxic cells, except that checkpoint-positive TILs were less prominent compared to DLBCL NOS. Cytotoxic TILs also interacted more with TILs and TAMs. A high amount of CD163+ TAM interactions with distinct TILs translated to unfavorable survival both in GCB DLBCL and T-DLBCL, whereas a high number of interactions between TILs and TAMs, CD4+ TILs and TAMs, and CD4+ TILs and other TILs associated with favorable outcomes only in T-DLBCL. Together, our data demonstrate biologically and clinically relevant differences in the composition of and cellular interactions in the TME between various DLBCL entities.
    DOI:  https://doi.org/10.3324/haematol.2024.286267
  9. Cancer Med. 2024 Dec;13(23): e70486
    LRP1B Suppresses Immunotherapy Efficacy in Lung Adenocarcinoma by Preventing Ferroptosis.
    Zi-Hao Ke, Ying Chen, Tao Yu, Qi Zhang, Yan Xiang, Kai-Hua Lu.
       BACKGROUND: Immune biomarkers for non-small-cell lung cancer (NSCLC) are programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). However, they cannot accurately predict the effectiveness of immunotherapy. Identifying appropriate biomarkers that can differentiate between beneficiary groups is imperative.
    METHODS: We identified lipoprotein receptor-related protein 1B (LRP1B) mutation as a potential biomarker for immunotherapy by analyzing clinical data, combined with bioinformatics analysis. The effects of LRP1B on ferroptosis were assessed using qRT-PCR, Western blotting, CCK-8 assay, and flow cytometry. The potential mechanism underlying the regulation of ferroptosis by LRP1B was elucidated using qRT-PCR, Western blotting, ChIP, and dual-luciferase reporter gene assays.
    RESULTS: Through the collection and analysis of clinical data, we had established that LRP1B mutations are closely associated with immunotherapy. Bioinformatics analysis revealed significant differences in the expression levels of PD-L1 and TMB between patients with LRP1B mutation and wild-type patients in lung adenocarcinoma (LUAD). Furthermore, we observed that patients with LRP1B mutation in LUAD had significantly higher levels of tumor-infiltrating lymphocytes (TILs) than wild-type patients. In addition, we found that patients with LRP1B mutation in LUAD had significantly prolonged progression-free survival (PFS) compared to wild-type patients. However, the differences of PD-L1 expression, TILs, and PFS were not observed in patients with LRP1B mutation in lung squamous cell carcinoma (LUSC). These findings provided strong evidence that LRP1B mutation was a potential biomarker for immunotherapy in LUAD. Moreover, our in vivo experiments indicated that knockdown of LRP1B enhanced the efficacy of mPD-1, and mechanistic studies revealed that LRP1B regulated the sensitivity of cells to ferroptosis by modulating the expression of SLC7A11 through altering the phosphorylation level of STAT3. Further analysis revealed that LRP1B knockdown promoted immunotherapy in vivo.
    CONCLUSIONS: Our results confirmed that LRP1B affected the efficacy of immunotherapy by modulating the sensitivity of NSCLC cells to ferroptosis. LRP1B mutations represent a highly promising immunotherapeutic biomarker for NSCLC.
    Keywords:  LRP1B; biomarker; ferroptosis; immunotherapy; lung cancer
    DOI:  https://doi.org/10.1002/cam4.70486
  10. Sci Adv. 2024 Dec 13. 10(50): eadm7928
    Ex vivo expansion and hydrogel-mediated in vivo delivery of tissue-resident memory T cells for immunotherapy.
    Shuyi Li, Zhi-Cheng Yao, Hanzhi Wang, Jonathan A Ecker, Mary O Omotoso, Jaechan Lee, Jiayuan Kong, Hexiang Feng, Worarat Chaisawangwong, Si-Sim Kang, Sydney R Shannon, Natalie K Livingston, Joan G Bieler, Shweta Singh, Maya L Zhang, Pilar O'Neal, Emily Ariail, Benjamin Biggs, John W Hickey, Hai-Quan Mao, Jonathan P Schneck.
      Tissue-resident memory T (TRM) cells preferentially reside in peripheral tissues, serving as key players in tumor immunity and immunotherapy. The lack of effective approaches for expanding TRM cells and delivering these cells in vivo hinders the exploration of TRM cell-mediated cancer immunotherapy. Here, we report a nanoparticle artificial antigen-presenting cell (nano-aAPC) ex vivo expansion approach and an in vivo delivery system for TRM cells. Using the nano-aAPC platform, we expanded functional antigen-specific murine and human TRM-like CD8+ T cells ex vivo. We also developed an injectable macroporous hyaluronic acid (HA) hydrogel to deliver TRM-like cells. TRM-like cells delivered in the optimized HA hydrogel trigger robust local and systemic antitumor immunity and show synergistic effects with anti-PD-1 treatment. Our findings suggest that nano-aAPC-induced TRM-like cells, coupled with a hydrogel delivery system, offer an efficient way to advance the understanding of TRM cell-mediated cancer therapy.
    DOI:  https://doi.org/10.1126/sciadv.adm7928
  11. Immunol Res. 2024 Dec 11. 73(1): 4
    The function of CD8 + T cells in the absence of MHC-I in target cells: what to learn from the deficiency of MHC-I expression in humans.
    Rafael Cardoso Maciel Costa Silva.
      
    DOI:  https://doi.org/10.1007/s12026-024-09556-8
  12. Neoplasia. 2024 Dec 05. pii: S1476-5586(24)00132-5. [Epub ahead of print]59 101091
    Tumor-Infiltrating Immune Cells in Colorectal Cancer.
    Sonia A M Ferkel, Elizabeth A Holman, Raoul S Sojwal, Samuel J S Rubin, Stephan Rogalla.
      Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.
    DOI:  https://doi.org/10.1016/j.neo.2024.101091
  13. Cancer Cell. 2024 Dec 06. pii: S1535-6108(24)00445-8. [Epub ahead of print]
    Breaking the mold: Unconventional T cells in cancer therapy.
    Yan-Ruide Li, Kuangyi Zhou, Yichen Zhu, Tyler Halladay, Lili Yang.
      Unconventional T cells, including invariant natural killer T (iNKT) cells, gamma delta (γδ) T cells, and mucosal-associated invariant T (MAIT) cells, play important roles in both innate and adaptive immunity. These cells respond to tumors rapidly and influence the tumor microenvironment (TME). Recent advances in understanding their biology, as well as the development of novel therapeutic approaches, have underscored their potential in cancer immunotherapy. This commentary will assess these advances and translational possibilities in the field.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.010
  14. Cancer Cell. 2024 Dec 03. pii: S1535-6108(24)00438-0. [Epub ahead of print]
    Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
    Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G Chen, Hong Zhu, Philip D Greenberg, Guideng Li.
      Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.003
  15. Nat Rev Clin Oncol. 2024 Dec 10.
    T cell dynamics with neoadjuvant immunotherapy in head and neck cancer.
    Maryann Zhao, Jonathan D Schoenfeld, Ann Marie Egloff, Glenn J Hanna, Robert I Haddad, Douglas R Adkins, Ravindra Uppaluri.
      Immune-checkpoint inhibitors (ICIs) are being tested as neoadjuvant therapies in various solid tumours, including in patients with head and neck squamous cell carcinoma (HNSCC), with promising results. Key findings thus far include that this approach is well-tolerated with favourable clinical outcomes including promising pathological response rates in initial studies. Pathological responses are likely to be increased by combining other agents with anti-PD-(L)1 antibodies. Comparisons of baseline biopsy samples with post-treatment surgical specimens have enabled correlative studies utilizing multiomic and immunogenomic methods. Data from these studies suggest that pretreatment intratumoural tissue-resident memory CD8+ T cells are key drivers of tumour regression and give rise to both local and systemic antitumour immune responses. Analyses of systemic responses have defined a PD-1+KLRG1- circulating CD8+ T cell subpopulation that is highly predictive of response, and revealed the interrelationships between intratumoural clones and circulating CD8+ T cells. Lastly, interrogation of T cell populations within lymph nodes is beginning to delineate the immune crosstalk between the primary tumour and tumour-draining lymph nodes and how this relationship might be disrupted with tumour infiltration of the latter. In this Review, we examine data from trials testing neoadjuvant ICIs in patients with HNSCC, focusing on human papillomavirus-unrelated disease, and highlight correlative immunogenomic findings from these trials.
    DOI:  https://doi.org/10.1038/s41571-024-00969-w
  16. Immunity. 2024 Dec 10. pii: S1074-7613(24)00529-6. [Epub ahead of print]57(12): 2717-2719
    T-switch-ing TCR specificity.
    Andrew Y Hu, Cristina Puig-Saus.
      Central tolerance restricts T cells that target self-antigens. In this issue of Immunity, Abdelfattah et al.1 describe a method to generate self-reactive T cell receptors (TCRs) by directed evolution of non-autoreactive TCRs to recognize self-antigen peptides and demonstrate potential for T cells engineered with such receptors in immunotherapy.
    DOI:  https://doi.org/10.1016/j.immuni.2024.11.014
  17. Cancer Cell. 2024 Dec 09. pii: S1535-6108(24)00437-9. [Epub ahead of print]42(12): 1997-2014
    Myeloid effector cells in cancer.
    Pieter Schol, Marit J van Elsas, Jim Middelburg, Maarten K Nijen Twilhaar, Thorbald van Hall, Tetje C van der Sluis, Sjoerd H van der Burg.
      The role of myeloid cells in tumor immunity is multifaceted. While dendritic cells support T cell-mediated tumor control, the highly heterogenous populations of macrophages, neutrophils, and immature myeloid cells were generally considered immunosuppressive. This view has led to effective therapies reinvigorating tumor-reactive T cells; however, targeting the immunosuppressive effects of macrophages and neutrophils to boost the cancer immunity cycle was clinically less successful. Recent studies interrogating the role of immune cells in the context of successful immunotherapy affirm the key role of T cells, but simultaneously challenge the idea that the cytotoxic function of T cells is the main contributor to therapy-driven tumor regression. Rather, therapy-activated intra-tumoral T cells recruit and activate or reprogram several myeloid effector cell types, the presence of which is necessary for tumor rejection. Here, we reappreciate the key role of myeloid effector cells in tumor rejection as this may help to shape future successful immunotherapies.
    Keywords:  M1 macrophages; cancer immunity cycle; eosinophils; immunotherapy; myeloid cells; neutrophils
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.002
  18. Front Immunol. 2024 ;15 1507218
    Decoding NY-ESO-1 TCR T cells: transcriptomic insights reveal dual mechanisms of tumor targeting in a melanoma murine xenograft model.
    Alaa Alsalloum, Saleh Alrhmoun, Olga Perik-Zavosdkaia, Marina Fisher, Marina Volynets, Julia Lopatnikova, Roman Perik-Zavodskii, Julia Shevchenko, Julia Philippova, Olga Solovieva, Evgenii Zavjalov, Vasily Kurilin, Hiroshi Shiku, Alexander Silkov, Sergey Sennikov.
      The development of T cell receptor-engineered T cells (TCR-T) targeting intracellular antigens is a promising strategy for treating solid tumors; however, the mechanisms underlying their effectiveness remain poorly understood. In this study, we employed advanced techniques to investigate the functional state of T cells engineered with retroviral vectors to express a TCR specific for the NY-ESO-1 157-165 peptide in the HLA-A*02:01 context. Flow cytometry revealed a predominance of naïve T cells. Gene expression profiling using NanoString technology revealed upregulation of genes encoding chemokine receptors CCR2 and CCR5, indicating enhanced migration towards tumor sites. In the SK-Mel-37 xenograft model, these transduced T cells achieved complete tumor eradication. Furthermore, single-cell RNA sequencing (scRNA-seq) conducted 14 days post-TCR T cell infusion provided a comprehensive analysis of the in vivo adaptation of these cells, identifying a distinct subset of CD8+ effector T cells with an NK cell-like gene expression profile. Our findings indicate that NY-ESO-1 TCR-transduced T cells have the potential to mediate dual antitumor effects through both antigen-independent NK-like and antigen-specific CTL-like responses. This study underscores the potential of NY-ESO-1 TCR-T cells as potent tumor-eradicating agents, highlighting the importance of harnessing their versatile functional capabilities to refine and enhance therapeutic strategies.
    Keywords:  NY-ESO-1; SK-Mel-37; TCR T cells; adoptive transfer; cancer-testis antigen; mice model; transcriptomics; xenograft
    DOI:  https://doi.org/10.3389/fimmu.2024.1507218
  19. J Nucl Med. 2024 Dec 12. pii: jnumed.124.268068. [Epub ahead of print]
    Preclinical Evaluation and Pilot Clinical Study of CD137 PET Radiotracer for Noninvasive Monitoring Early Responses of Immunotherapy.
    Kai Cheng, Luna Ge, Miaomiao Song, Wanhu Li, Jinsong Zheng, Jingru Liu, Yuxi Luo, Pengfei Sun, Shengnan Xu, Zhen Cheng, Jinming Yu, Jie Liu.
      Given the variability in the effectiveness of immune checkpoint blocking therapy among patients and tumor types, development of noninvasive methods for longitudinal assessment of immune cell function and early tumor response is crucial for precision immunotherapy. CD137 (4-1BB), a marker of activated T cells, plays a significant role in immunotherapy. However, its potential as an imaging biomarker for activated T cells in the tumor microenvironment has not been explored. This study introduces a bicyclic peptide-based probe that targets CD137 for noninvasive PET imaging of tumor-infiltrating activated T cells. Methods: A bicyclic peptide-based probe, [18F]AlF-NOTA-BCP137, was first designed and synthesized for quantitative and longitudinal whole-body visualization of CD137 dynamics. Initially, [18F]AlF-NOTA-BCP137 was assessed in mouse models with varying CD137 expression levels. Next, [18F]AlF-NOTA-BCP137 was used for longitudinal monitoring of systemic CD137 changes in a humanized tumor-bearing mouse model. Lastly, the probe was further evaluated in a small group of patients with hepatocellular carcinoma undergoing immunotherapy or combination immunotherapy. Results: [18F]AlF-NOTA-BCP137 PET accurately characterized CD137 expression in homologous transplanted mouse models and tumor patients. The findings from animal studies indicated that uptake of [18F]AlF-NOTA-BCP137 was predictive of the early therapeutic response to combination immunotherapies and was positively associated with the increased survival rates of mice with tumors. A preliminary clinical study involving small patient cohorts demonstrated that [18F]AlF-NOTA-BCP137 imaging effectively predicted early patient responses to immunotherapeutic interventions. Conclusion: [18F]AlF-NOTA-BCP137 PET imaging of CD137 is a promising and reliable method for evaluating the efficacy of multiple combination immunotherapies and merits further validation in larger-scale clinical trials. This approach has the potential for early noninvasive visualization of individual patient responses in combination cancer immunotherapy and will aid in tailoring personalized strategies for patients.
    Keywords:  CD137; PET imaging; activated T cells; immunotherapy
    DOI:  https://doi.org/10.2967/jnumed.124.268068
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